ORCID Profile
0000-0002-4741-3035
Current Organisation
University of Technology Sydney
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Publisher: American Physiological Society
Date: 2017
DOI: 10.1152/AJPLUNG.00200.2016
Abstract: the aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-deficient ( Tnfsf10 −/− ) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10 −/− mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID 50 ). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID 50 . HDM-challenged Tnfsf10 −/− mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10 −/− mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-λ2/3 but not IFN-α or IFN-β. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Springer Singapore
Date: 2020
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.CBI.2018.12.009
Abstract: Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.
Publisher: Cambridge University Press (CUP)
Date: 06-2005
DOI: 10.1017/S095410200500266X
Abstract: The McDonald Islands (53°S, 73°E) originally comprised three small islands that lie on the Kerguelen Plateau, 44 km west of Heard Island. No volcanic activity was observed since their discovery in 1874 until 1997, when two passing ships recorded major changes and eruptive behaviour. A 2001 satellite image showed that the main island had doubled its area. This paper reports observations made from a cruise ship in November 2002, supplemented by a high-resolution satellite image acquired in March 2003. A new volcanic complex comprises lava domes, spines and flows, all assumed to be phonolitic, similar to the older volcanic rocks. The complex shows dormant volcanic activity, with numerous fumaroles, recent spine evolution and lava flows. Changes in relative sea level have connected Flat and McDonald Islands. A spit about 1km long with extensive shoals beyond, now extends eastward from McDonald Island and presents new hazards to shipping. Biological changes include colonization by king penguins ( Aptenodytes patagonica ), previously absent, and a large reduction in numbers of formerly widespread macaroni penguins ( Eudyptes chrysolophus chrysolophus ).
Publisher: Springer Science and Business Media LLC
Date: 02-04-2015
DOI: 10.1038/SREP09496
Abstract: Fibulin-1 is an extracellular matrix (ECM) protein, levels of which are elevated in serum and lung tissue from patients with idiopathic pulmonary fibrosis compared to healthy volunteers. Inhibition of fibulin-1C, one of four fibulin-1 isoforms, reduced proliferation and wound healing in human airway smooth muscle (ASM) cells. This study identified the bioactive region/s of fibulin-1C which promotes fibrosis. Seven fibulin-1C peptides were synthesized and used to pre-coat tissue culture plates before lung derived ASM cells and fibroblasts from patients with pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD) or neither disease (Control) were plated. Peptide effects on in vitro measures of fibrosis: cell attachment, proliferation and viability and ECM deposition, were examined. Among these peptides, peptide 1C1 (FBLN1C1) enhanced ASM cell and fibroblast attachment. FBLN1C1 increased mitochondrial activity and proliferation in fibroblasts. In addition, FBLN1C1 stimulated fibulin1 deposition in PF and COPD fibroblasts and augmented fibronectin and perlecan deposition in all three groups. Peptides FBLN1C2 to FBLN1C7 had no activity. The active fibulin-1C peptide identified in this study describes a useful tool for future studies. Ongoing investigation of the role of fibulin-1 may reveal the mechanisms underlying the pathphysiology of chronic lung diseases.
Publisher: Bentham Science Publishers Ltd.
Date: 19-12-2019
DOI: 10.2174/1568026619666191026105308
Abstract: Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence system utilizes a wide array of the cells, proteins and chemical signals that are distributed in blood and tissues which further constitute the innate and adaptive immune system. The lack of antifungal agents and their limited therapeutic effects have led to high mortality and morbidity related to such infections. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. This article sheds light on novel drug delivery approaches to target the immunological axis for several Candida species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. rugose, C. hemulonii, etc.). It is clear that the novel drug delivery approaches include vaccines, adoptive transfer of primed immune cells, recombinant cytokines, therapeutic antibodies, and nanoparticles, which have immunomodulatory effects. Such advancements in targeting various underpinning mechanisms using the concept of novel drug delivery will provide a new dimension to the fungal infection clinic particularly due to Candida species with improved patient compliance and lesser side effects. This advancement in knowledge can also be extended to target various other similar microbial species and infections.
Publisher: American Society for Clinical Investigation
Date: 22-08-2019
Publisher: IOP Publishing
Date: 08-04-2021
Abstract: Obstructive sleep apnea (OSA) is a chronic disorder that involves a decrease or complete cessation of airflow during sleep. It occurs when the muscles supporting the soft tissues in the throat relax during sleep, causing narrowing or closure of the upper airway. Sleep apnea is a serious medical condition with an increased risk of cardiovascular complications and impaired quality of life. Continuous positive airway pressure (CPAP) is the most effective treatment for moderate to severe cases of OSA and is effective in mild sleep apnea. However, CPAP therapy is associated with the development of several nasal side effects and is inconvenient for the user, leading to low compliance rates. The effects of CPAP treatment on the upper respiratory system, as well as the pathogenesis of side effects, are incompletely understood and not adequately researched. To better understand the effects of CPAP treatment on the upper respiratory system, we developed an in vitro 3D-printed microfluidic platform. A nasal epithelial cell line, RPMI 2650, was then exposed to certain conditions to mimic the in vivo environment. To create these conditions, the microfluidic device was utilized to expose nasal epithelial cells grown and differentiated at the air–liquid interface. The airflow was similar to what is experienced with CPAP, with pressure ranging between 0 and 20 cm of H 2 O. Cells exposed to pressure showed decreased barrier integrity, change in cellular shape, and increased cell death (lactate dehydrogenase release into media) compared to unstressed cells. Stressed cells also showed increased secretions of inflammatory markers IL-6 and IL-8 and had increased production of ATP. Our results suggest that stress induced by airflow leads to structural, metabolic, and inflammatory changes in the nasal epithelium, which may be responsible for developing nasal side-effects following CPAP treatment.
Publisher: MDPI AG
Date: 09-05-2022
DOI: 10.3390/MOLECULES27093038
Abstract: The inflammatory response is a central aspect of the human immune system that acts as a defense mechanism to protect the body against infections and injuries. A dysregulated inflammatory response is a major health concern, as it can disrupt homeostasis and lead to a plethora of chronic inflammatory conditions. These chronic inflammatory diseases are one of the major causes of morbidity and mortality worldwide and the need for them to be managed in the long term has become a crucial task to alleviate symptoms and improve patients’ overall quality of life. Although various synthetic anti-inflammatory agents have been developed to date, these medications are associated with several adverse effects that have led to poor therapeutic outcomes. The hunt for novel alternatives to modulate underlying chronic inflammatory processes has unveiled nature to be a plentiful source. One such ex le is agarwood, which is a valuable resinous wood from the trees of Aquilaria spp. Agarwood has been widely utilized for medicinal purposes since ancient times due to its ability to relieve pain, asthmatic symptoms, and arrest vomiting. In terms of inflammation, the major constituent of agarwood, agarwood oil, has been shown to possess multiple bioactive compounds that can regulate molecular mechanisms of chronic inflammation, thereby producing a multitude of pharmacological functions for treating various inflammatory disorders. As such, agarwood oil presents great potential to be developed as a novel anti-inflammatory therapeutic to overcome the drawbacks of existing therapies and improve treatment outcomes. In this review, we have summarized the current literature on agarwood and its bioactive components and have highlighted the potential roles of agarwood oil in treating various chronic inflammatory diseases.
Publisher: Wiley
Date: 02-04-2013
DOI: 10.1111/IMR.12058
Abstract: Chronic inflammatory diseases of the lung are leading causes of morbidity and mortality worldwide. Many of these disorders can be attributed to abnormal immune responses to environmental stimuli and infections. As such, understanding the innate host defense pathways and their regulatory systems will be critical to developing new approaches to treatment. In this regard, there is increasing interest in the role of microRNAs (miRNAs) in the regulation of pulmonary innate host defense responses and the inflammatory sequelae in respiratory disease. In this review, we discuss recent findings that indicate an important role for miRNAs in the regulation in mouse models of various respiratory diseases and in host defense against bacterial and viral infection. We also discuss the potential utility and limitations of targeting these molecules as anti-inflammatory strategies and also as a means to improve pathogen clearance from the lung.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.MOLIMM.2017.01.014
Abstract: Innate immune responses act as first line defences upon exposure to potentially noxious stimuli. The innate immune system has evolved numerous intracellular and extracellular receptors that undertake surveillance for potentially damaging particulates. Inflammasomes are intracellular innate immune multiprotein complexes that form and are activated following interaction with these stimuli. Inflammasome activation leads to the cleavage of pro-IL-1β and release of the pro-inflammatory cytokine, IL-1β, which initiates acute phase pro-inflammatory responses, and other responses are also involved (IL-18, pyroptosis). However, excessive activation of inflammasomes can result in chronic inflammation, which has been implicated in a range of chronic inflammatory diseases. The airways are constantly exposed to a wide variety of stimuli. Inflammasome activation and downstream responses clears these stimuli. However, excessive activation may drive the pathogenesis of chronic respiratory diseases such as severe asthma and chronic obstructive pulmonary disease. Thus, there is currently intense interest in the role of inflammasomes in chronic inflammatory lung diseases and in their potential for therapeutic targeting. Here we review the known associations between inflammasome-mediated responses and the development and exacerbation of chronic lung diseases.
Publisher: Elsevier BV
Date: 07-2020
Publisher: The American Association of Immunologists
Date: 05-2013
DOI: 10.4049/JIMMUNOL.190.SUPP.62.13
Abstract: Steroid-resistant asthma is an important clinical problem and effective therapies are urgently required. Macrolides have been shown to be efficacious in treating steroid-resistant forms of asthma. However, how these immunomodulatory antibiotics induce their effects is not known. Using mouse models of Chlamydia and Haemophilus lung infection and ovalbumin-induced allergic airway disease (AAD) we have previously shown that both infections induce airways hyperresponsiveness (AHR) and neutrophilic inflammation in AAD that is resistant to steroid treatment. In the current study the effects of clarithromycin versus amoxicillin on immune responses in Th2-associated, steroid-sensitive eosinophilic and infection-induced, Th1/Th17-associated, steroid-resistant neutrophilic AAD was assessed. We show that clarithromycin, but not amoxicillin, treatment reduces AHR and inflammation in both steroid-sensitive and steroid-resistant AAD. Suppression of these features of disease was associated with a reduction in a number of Th1, Th2 and Th17-associated immune factors. Significantly, clarithromycin treatment reduced Th2-associated factors in steroid-sensitive AAD and Th1/Th17-associated factors in infection-induced, steroid-resistant AAD. These findings suggest that macrolide treatment can have broad anti-inflammatory effects on immune responses in the asthmatic lung and that the specific immune responses that are suppressed may be dependent on the responses that predominate during disease.
Publisher: Elsevier BV
Date: 10-2015
Publisher: MDPI AG
Date: 17-02-2023
DOI: 10.3390/NU15041019
Abstract: Chronic obstructive pulmonary disease (COPD) is an irreversible inflammatory respiratory disease characterized by frequent exacerbations and symptoms such as cough and wheezing that lead to irreversible airway damage and hyperresponsiveness. The primary risk factor for COPD is chronic cigarette smoke exposure, which promotes oxidative stress and a general pro-inflammatory condition by stimulating pro-oxidant and pro-inflammatory pathways and, simultaneously, inactivating anti-inflammatory and antioxidant detoxification pathways. These events cause progressive damage resulting in impaired cell function and disease progression. Treatments available for COPD are generally aimed at reducing the symptoms of exacerbation. Failure to regulate oxidative stress and inflammation results in lung damage. In the quest for innovative treatment strategies, phytochemicals, and complex plant extracts such as agarwood essential oil are promising sources of molecules with antioxidant and anti-inflammatory activity. However, their clinical use is limited by issues such as low solubility and poor pharmacokinetic properties. These can be overcome by encapsulating the therapeutic molecules using advanced drug delivery systems such as polymeric nanosystems and nanoemulsions. In this study, agarwood oil nanoemulsion (agarwood-NE) was formulated and tested for its antioxidant and anti-inflammatory potential in cigarette smoke extract (CSE)-treated BCi-NS1.1 airway basal epithelial cells. The findings suggest successful counteractivity of agarwood-NE against CSE-mediated pro-inflammatory effects by reducing the expression of the pro-inflammatory cytokines IL-1α, IL-1β, IL-8, and GDF-15. In addition, agarwood-NE induced the expression of the anti-inflammatory mediators IL-10, IL-18BP, TFF3, GH, VDBP, relaxin-2, IFN-γ, and PDGF. Furthermore, agarwood-NE also induced the expression of antioxidant genes such as GCLC and GSTP1, simultaneously activating the PI3K pro-survival signalling pathway. This study provides proof of the dual anti-inflammatory and antioxidant activity of agarwood-NE, highlighting its enormous potential for COPD treatment.
Publisher: American Thoracic Society
Date: 15-09-2021
Publisher: Wiley
Date: 26-06-2012
Publisher: Wiley
Date: 16-07-2019
DOI: 10.1002/DDR.21571
Abstract: Lung diseases are the leading cause of mortality worldwide. The currently available therapies are not sufficient, leading to the urgent need for new therapies with sustained anti-inflammatory effects. Small/short or silencing interfering RNA (siRNA) has potential therapeutic implications through post-transcriptional downregulation of the target gene expression. siRNA is essential in gene regulation, so is more favorable over other gene therapies due to its small size, high specificity, potency, and no or low immune response. In chronic respiratory diseases, local and targeted delivery of siRNA is achieved via inhalation. The effectual delivery can be attained by the generation of aerosols via inhalers and nebulizers, which overcomes anatomical barriers, alveolar macrophage clearance and mucociliary clearance. In this review, we discuss the different siRNA nanocarrier systems for chronic respiratory diseases, for safe and effective delivery. siRNA mediated pro-inflammatory gene or miRNA targeting approach can be a useful approach in combating chronic respiratory inflammatory conditions and thus providing sustained drug delivery, reduced therapeutic dose, and improved patient compliance. This review will be of high relevance to the formulation, biological and translational scientists working in the area of respiratory diseases.
Publisher: American Thoracic Society
Date: 15-02-2019
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.IAC.2014.01.001
Abstract: Tetramer-forming tryptase (hTryptase-β) was recently discovered to have a prominent role in preventing the internal accumulation of life-threatening fibrin deposits and fibrin-platelet clots. The anticoagulant activity of hTryptase-β is an explanation for the presence of hemorrhagic disorders in some patients with anaphylaxis or mastocytosis. The fragments of hFibrinogen formed by the proteolysis of this prominent protein by hTryptase-β could be used as biomarkers in the blood and/or urine for the identification and monitoring of patients with mast cell-dependent disorders. Recombinant hTryptase-β has potential to be used in clinical settings where it is desirable to inhibit blood coagulation.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Future Science Ltd
Date: 08-2021
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Oxford University Press (OUP)
Date: 30-09-2014
Abstract: What are the effects on fertility of cigarette smoke-induced toxicity on male offspring exposed during the gestational/weaning period? Maternal cigarette smoke exposure during the gestational/weaning period causes long-term defects in male offspring fertility. Cigarette smoke is a well-known reproductive toxicant which is particularly harmful to both fetal and neonatal germ cells. However, recent studies suggest a significant portion of young mothers in the developed world still smoke during pregnancy. In the context of male reproductive health, our understanding of the effects of in utero exposure on offspring fertility is limited. In this study, 27 C57BL/6 5-week-old female mice were exposed via the nose-only to cigarette smoke (treatment) or 27 were exposed to room air (control) for 6 weeks before being housed with stud males to produce litters. In the treatment group, smoke exposure continued throughout mating, pregnancy and lactation until weaning of pups at 21 days post birth. Male offspring were examined at post-natal days 3, 6, 12, 21 and 98 (adult). Approximately 108 maternal smoke-exposed C57BL/6 offspring and controls were examined. Spermatogenesis was examined using testicular histology and apoptosis/DNA damage was assessed using caspase immunohistochemistry and TUNEL. Sertoli cell morphology and fluctuations in the spermatogonial stem cell population were also examined using immunohistochemistry. Microarray and QPCR analysis were performed on adult testes to examine specific long-term transcriptomic alteration as a consequence of maternal smoke exposure. Sperm counts and motility, zona/oolemma binding assays, COMET analysis and mitochondrial genomic sequencing were also performed on spermatozoa obtained from adult treated and control mice. Fertility trials using exposed adult male offspring were also performed. Maternal cigarette smoke exposure caused increased gonocyte and meiotic spermatocyte apoptosis (P < 0.01) as well as germ cell depletion in the seminiferous tubules of neonatal and juvenile offspring. Aberrant testicular development characterized by abnormal Sertoli and germ cell organization, a depleted spermatogonial stem cell population (P < 0.01), atrophic seminiferous tubules and increased germ cell DNA damage (P < 0.01) persisted in adult offspring 11 weeks after exposure. Microarray analysis of adult offspring testes associated these defects with meiotic germ cell development, sex hormone metabolism, oxidative stress and Sertoli cell signalling. Next generation sequencing also revealed a high mitochondrial DNA mutational load in the testes of adult offspring (P < 0.01). Adult maternal smoke-exposed offspring also had reduced sperm counts with spermatozoa exhibiting morphological abnormalities (P < 0.01), affecting motility and fertilization potential. Odf2, a spermatozoa flagellum component required for coordinated ciliary beating, was also significantly down-regulated (P < 0.01) in maternal smoke-exposed adult offspring, with aberrant localization along the spermatozoa flagellum. Adult maternal smoke-exposed offspring took significantly longer to impregnate control females and had a slight but significant (P < 0.01) reduction in litter size. This study examined only one species (mouse) using a smoking model which only simulates human cigarette smoke exposure. This study represents the first comprehensive animal model of maternal smoking on male offspring reproductive function, suggesting that exposure during the gestational/weaning period causes long-term defects in male offspring fertility. This is due to a compromised spermatogonial stem cell population resulting from gonocyte apoptosis and impaired spermatogenic development. This results in significant germ cell damage and Sertoli cell dysfunction, impacting germ cell number, tubule organization, DNA damage and spermatozoa in adult offspring. This study strengthens the current literature suggesting that maternal exposure impairs male offspring fertility, which is currently debated due to conflicting studies. This study was funded by the Australian Research Council, Hunter Medical Research Institute, National Health and Medical Research Council of Australia and the Newcastle Permanent Building Society Charitable Trust. The authors declare no conflict of interest.
Publisher: MDPI AG
Date: 28-04-2022
Abstract: Cigarette smoke is considered a primary risk factor for chronic obstructive pulmonary disease. Numerous toxicants present in cigarette smoke are known to induce oxidative stress and airway inflammation that further exacerbate disease progression. Generally, the broncho-epithelial cells and alveolar macrophages exposed to cigarette smoke release massive amounts of oxidative stress and inflammation mediators. Chronic exposure of cigarette smoke leads to premature senescence of airway epithelial cells. This impairs cellular function and ultimately leads to the progression of chronic lung diseases. Therefore, an ideal therapeutic candidate should prevent disease progression by controlling oxidative stress, inflammation, and senescence during the initial stage of damage. In our study, we explored if berberine (an alkaloid)-loaded liquid crystalline nanoparticles (berberine-LCNs)-based treatment to human broncho-epithelial cells and macrophage inhibits oxidative stress, inflammation, and senescence induced by cigarette-smoke extract. The developed berberine-LCNs were found to have favourable physiochemical parameters, such as high entrapment efficiency and sustained in vitro release. The cellular-assay observations revealed that berberine-LCNs showed potent antioxidant activity by suppressing the generation of reactive oxygen species in both broncho-epithelial cells (16HBE) and macrophages (RAW264.7), and modulating the genes involved in inflammation and oxidative stress. Similarly, in 16HBE cells, berberine-LCNs inhibited the cigarette smoke-induced senescence as revealed by X-gal staining, gene expression of CDKN1A (p21), and immunofluorescent staining of p21. Further in-depth mechanistic investigations into antioxidative, anti-inflammatory, and antisenescence research will ersify the current findings of berberine as a promising therapeutic approach for inflammatory lung diseases caused by cigarette smoking.
Publisher: Public Library of Science (PLoS)
Date: 15-03-2011
Publisher: Springer International Publishing
Date: 14-08-2020
Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2022
DOI: 10.1101/2022.10.19.512954
Abstract: Emerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells (PBMCs) of convalescent patients using SARS-CoV-2 receptor binding domains (RBDs) carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and class 5). Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (mAb S309) by orders of magnitude. They also provide potent prophylactic and therapeutic in vivo protection of hACE2 mice against viral challenge. Our results indicate that exposure to Wuhan SARS-CoV-2 induces antibodies that maintain potent and broad neutralization against emerging VOCs using two unique strategies: either by targeting the ergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14) or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). Our results provide guidance for next generation monoclonal antibody development and vaccine design.
Publisher: Wiley
Date: 26-10-2015
DOI: 10.1111/AVJ.12379
Abstract: Avian influenza viruses (AIVs) are found worldwide in numerous bird species, causing significant disease in gallinaceous poultry and occasionally other species. Surveillance of wild bird reservoirs provides an opportunity to add to the understanding of the epidemiology of AIVs. This study examined key findings from the National Avian Influenza Wild Bird Surveillance Program over a 5-year period (July 2007-June 2012), the main source of information on AIVs circulating in Australia. The overall proportion of birds that tested positive for influenza A via PCR was 1.9 ± 0.1%, with evidence of widespread exposure of Australian wild birds to most low pathogenic avian influenza (LPAI) subtypes (H1-13, H16). LPAI H5 subtypes were found to be dominant and widespread during this 5-year period. Given Australia's isolation, both geographically and ecologically, it is important for Australia not to assume that the epidemiology of AIV from other geographic regions applies here. Despite all previous highly pathogenic avian influenza outbreaks in Australian poultry being attributed to H7 subtypes, widespread detection of H5 subtypes in wild birds may represent an ongoing risk to the Australian poultry industry.
Publisher: American Thoracic Society
Date: 06-2202
Publisher: Future Medicine Ltd
Date: 05-2022
Abstract: Pulmonary diseases such as lung cancer, asthma and tuberculosis have remained one of the common challenges globally. Polymeric micelles (PMs) have emerged as an effective technique for achieving targeted drug delivery for a local as well as a systemic effect. These PMs encapsulate and protect hydrophobic drugs, increase pulmonary targeting, decrease side effects and enhance drug efficacy through the inhalation route. In the current review, emphasis has been placed on the different barriers encountered by the drugs given via the pulmonary route and the mechanism of PMs in achieving drug targeting. The applications of PMs in different pulmonary diseases have also been discussed in detail.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.VACCINE.2012.03.084
Abstract: Many animal and human studies have found an inverse association between anti-oxidized low-density lipoprotein (oxLDL) antibodies (anti-oxLDL) and atherosclerotic burden. Furthermore, anti-oxLDL antibodies have been shown to cause regression of atherosclerotic plaque in mice. Animal studies indicate that the 23-valent pneumococcal vaccine may induce the production of these potentially protective anti-oxLDL antibodies, and human epidemiological studies support their potentially beneficial effect in reducing cardiovascular events. Here we describe the association between self-reported pneumococcal vaccination, vaccination verified by linkage to health records, and anti-pneumococcal antibody titers, and anti-ox-LDL titers in a group of 116 older people. We found a bimodal distribution of anti-oxLDL antibodies, and a significant association between pneumococcal IgG and anti-oxLDL antibody titers that remained after multivariate adjustment for potential confounders (p=0.04). There was no significant association between self-reported vaccination or vaccination verified by health record linkage and ox-LDL titers, which may be due to reporting error or variability in response to the vaccine. These results support a mechanistic link between pneumococcal vaccination and a potential protective effect on cardiovascular disease, and indicate that self-reported or verified vaccine status may not be sufficient to detect this association.
Publisher: BMJ
Date: 11-1995
Abstract: The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in a small proportion of cases. We report here that one of these, the Arg163Cys substitution, does not cosegregate with MH susceptibility. Comparison of cDNA sequences encoding the skeletal muscle specific components of the dihydropyridine receptor alpha 1 subunit between MH susceptible (MHS) and MH non-susceptible (MHN) patients was made in subjects without the reported MH linked RYR1 mutations. There were no differences within the sequence encoding the II-III loop or the IS3/IS3-IS4 segment, excluding defects in these functional segments of the alpha 1 subunit as frequent causes of MH.
Publisher: BMJ
Date: 21-10-2010
Abstract: Infections with some bacteria, including Streptococcus pneumoniae, have been associated with a reduced incidence of asthma. Components of S pneumoniae may have the potential to modulate allergic inflammatory responses and suppress the development of asthma. To determine if human S pneumoniae vaccines have the potential to suppress asthma by elucidating their effect on allergic airways disease (AAD) in mouse models. AAD was induced in BALB/c mice by intraperitoneal sensitisation and intranasal challenge with ovalbumin. Pneumococcal conjugate or polysaccharide vaccines were administered at the time of sensitisation or during established AAD. Hallmark features of AAD were assessed. Levels of regulatory T cells (Tregs) were quantified by fluorescence-activated cell sorting, and their immunoregulatory capacity was assessed using proliferation assays and anti-CD25 antibody treatment. Intranasal administration of the conjugate vaccine, but not the polysaccharide vaccine, suppressed the hallmark features of AAD, including: eosinophilic and T helper 2-mediated inflammation airway hyper-responsiveness circulating immunoglobulin E (IgE) levels and mucus hypersecretion. Intramuscular administration of the conjugate vaccine had limited protective effects. The conjugate vaccine increased Tregs in the lung-draining lymph nodes, lung and spleen. Furthermore, conjugate vaccine-induced Tregs had an enhanced capacity to suppress T effector responses. Anti-CD25 administration reversed the suppressive effects of the conjugate vaccine. A currently available human conjugate vaccine suppresses the hallmark features of AAD through the induction of Tregs. Thus targeted administration may provide a novel immunoregulatory treatment for asthma.
Publisher: Springer Singapore
Date: 2019
Publisher: MDPI AG
Date: 23-10-2022
DOI: 10.3390/FERMENTATION8110572
Abstract: Lactic acid bacteria are one of the potential natural remedies used worldwide, commonly known as probiotics. Here, the aim of this research investigation was to isolate a probiotic Lactobacilli strain, YLM015, from the popular Korean fermented vegetable “Kimchi” and to evaluate its anti-viral potential against influenza virus A (IFVA) H1N1 using the MDCK cell line in vitro, and in embryonated eggs in ovo. The YML015 strain was selected from among the 1200 Lactobacilli isolates for further studies based on its potent anti-viral efficacy. YML015 was identified and characterized as Lactoplantibacillus plantarum YML015 based on the 16S rRNA gene sequencing and biochemically with an API 50 CHL Kit. In ovo assay experienced with embryonated eggs and the hemagglutination inhibition method, as well as cytopathogenic reduction assay, was performed in idually to observe anti-influenza viral activity of YML015 against influenza virus A H1N1. Additionally, YML015 was classified for its non-resistance nature as safe for humans and animals as confirmed by the antibiotic susceptibility (MIC) test, cell viability, and hemolysis assay. The heat stability test was also experienced by using different heat-treated cell-free supernatant (CFS) s les of YML015. As a result, YML015 showed highly potent anti-viral activity against influenza virus A H1N1 in vitro in the MDCK cell line. Overall findings suggest that anti-influenza viral activity of L. plantarum YML015 makes it a potential candidate of choice for use as an influential probiotic in pharmacological preparations to protect humans and animals from flu and viral infection.
Publisher: Portland Press Ltd.
Date: 08-05-2015
DOI: 10.1042/CS20140654
Abstract: Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a short-term mouse model that reproduced the hallmark features of RV-induced exacerbation of COPD. Evaluation of complex protocols involving multiple dose elastase and lipopolysaccharide (LPS) administration combined with RV1B infection showed suppression rather than enhancement of inflammatory parameters compared with control mice infected with RV1B alone. Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects. In contrast, a single elastase treatment followed by RV infection led to heightened airway neutrophilic and lymphocytic inflammation, increased expression of tumour necrosis factor (TNF)-α, C-X-C motif chemokine 10 (CXCL10)/IP-10 (interferon γ-induced protein 10) and CCL5 [chemokine (C-C motif) ligand 5]/RANTES (regulated on activation, normal T-cell expressed and secreted), mucus hypersecretion and preliminary evidence for increased airway hyper-responsiveness compared with mice treated with elastase or RV infection alone. In summary, we have developed a new mouse model of RV-induced COPD exacerbation that mimics many of the inflammatory features of human disease. This model, in conjunction with human models of disease, will provide an essential tool for studying disease mechanisms and allow testing of novel therapies with potential to be translated into clinical practice.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CBI.2019.108732
Abstract: The human body is a home to thousands of microbiotas. It is defined as a community of symbiotic, commensal and pathogenic microorganisms that have existed in all exposed sites of the body, which have co-evolved with diet, lifestyle, genetic factors and immune factors. Human microbiotas have been studied for years on their effects with relation to health and diseases. Relevant published studies, literature and reports were searched from accessible electronic databases and related institutional databases. We used keywords, viz microbiome, microbiota, microbiome drug delivery and respiratory disease. Selected articles were carefully read through, clustered, segregated into subtopics and reviewed. The traditional belief of sterile lungs was challenged by the emergence of culture-independent molecular techniques and the recently introduced invasive broncho-alveolar lavage (BAL) s ling method. The constitution of a lung microbiome mainly depends on three main ecological factors, which include firstly, the immigration of microbes into airways, secondly, the removal of microbes from airways and lastly, the regional growth conditions. In healthy conditions, the microbial communities that co-exist in our lungs can build significant pulmonary immunity and could act as a barrier against diseases, whereas, in an adverse way, microbiomes may interact with other pathogenic bacteriomes and viromes, acting as a cofactor in inflammation and host immune responses, which may lead to the progression of a disease. Thus, the use of microbiota as a target, and as a drug delivery system in the possible modification of a disease state, has started to gain massive attention in recent years. Microbiota, owing to its unique characteristics, could serve as a potential drug delivery system, that could be bioengineered to suit the interest. The engineered microbiome-derived therapeutics can be delivered through BC, bacteriophage, bacteria-derived lipid vesicles and microbe-derived extracellular vesicles. This review highlights the relationships between microbiota and different types of respiratory diseases, the importance of microbiota towards human health and diseases, including the role of novel microbiome drug delivery systems in targeting various respiratory diseases.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.BIOPHA.2018.11.051
Abstract: In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such ex le that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.AHJ.2016.04.003
Abstract: Research has shown that vaccination with Streptococcus pneumoniae reduced the extent of atherosclerosis in experimental animal models. It is thought that phosphorylcholine lipid antigens in the S. pneumoniae cell wall induce the production of antibodies that cross-react with oxidized low-density lipoprotein, a component of atherosclerotic plaques. These antibodies may bind to and facilitate the regression of the plaques. Available data provide evidence that similar mechanisms also occur in humans, leading to the possibility that pneumococcal vaccination protects against atherosclerosis. A systematic review and meta-analysis, including 8 observational human studies, of adult pneumococcal polysaccharide vaccination for preventing cardiovascular disease in people older than 65 years, showed a 17% reduction in the odds (odds ratio 0.83, 95% CI 0.71-0.97) of having an acute coronary syndrome event. The AUSPICE is a multicenter, randomized, placebo-controlled, double-blind, clinical trial to formally test whether vaccination with the pneumococcal polysaccharide vaccine protects against cardiovascular events (fatal and nonfatal acute coronary syndromes and ischemic strokes). Cardiovascular outcomes will be obtained during 4 to 5 years of follow-up, through health record linkage with state and national administrative data sets. This is the first registered randomized controlled trial (on US, World Health Organization, Australia and New Zealand trial registries) to be conducted to test whether vaccination with the pneumococcal polysaccharide vaccine will reduce cardiovascular events. If successful, vaccination can be readily extended to at-risk groups to reduce the risk of cardiovascular diseases.
Publisher: Elsevier BV
Date: 05-1994
Abstract: In this investigation we report the presence of two forms of inositol (1,4,5)P3/(1,3,4,5)P4-polyphosphate 5-phosphatase activity (types I and II) which were observed in soluble extracts of skeletal muscle after fractionation by DEAE-Sephacel chromatography. Hydrolysis of D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and D-myo-inositol 1,3,4,5-tetrakisphosphate by both phosphatases was 5-phosphate-specific, Mg2+ ion-dependent and inhibited by D-2,3-bisphosphoglycerate. Soluble type I 5-phosphatase activity was purified 27,300-fold to a specific activity of 2.54 mumol of Ins(1,4,5)P3 hydrolyzed/min/mg protein after a combination of DEAE-Sephacel, Blue Sepharose, heparin-agarose and structural analogue affinity chromatography. Purified type I 5-phosphatase had an apparent mean Km of 8.9 and 1.1 microM and Vmax of 3.55 and 0.13 mumol of substrate hydrolyzed/min/mg protein for Ins(1,4,5)P3 and Ins(1,3,4,5)P4, respectively. Investigations on soluble type II 5-phosphatase after DEAE-Sephacel chromatography indicated an apparent Km of 71.4 microM Ins(1,4,5)P3 and an apparent molecular mass of 81 kDa. Soluble type I phosphatase has an apparent molecular mass of 48 kDa and an isoelectric point of 5.8. Soluble type I 5-phosphatase has kinetic constants which suggest a role in the regulation of inositol polyphosphates at physiological concentrations. These results support a role for Ins(1,4,5)P3 in the regulation of Ca2+ homeostasis in skeletal muscle.
Publisher: Future Science Ltd
Date: 02-2022
Abstract: Chronic respiratory disorders affect millions of people worldwide. Pathophysiological changes to the normal airway wall structure, including changes in the composition and organization of its cellular and molecular constituents, are referred to as airway remodeling. The inadequacy of effective treatment strategies and scarcity of novel therapies available for the treatment and management of chronic respiratory diseases have given rise to a serious impediment in the clinical management of such diseases. The progress made in advanced drug delivery, has offered additional advantages to fight against the emerging complications of airway remodeling. This review aims to address the gaps in current knowledge about airway remodeling, the relationships between remodeling, inflammation, clinical phenotypes and the significance of using novel drug delivery methods.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2021
DOI: 10.1038/S41541-021-00406-4
Abstract: Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.
Publisher: Elsevier BV
Date: 03-2017
Publisher: Future Medicine Ltd
Date: 03-2022
Publisher: Informa UK Limited
Date: 05-2017
DOI: 10.2147/COPD.S138612
Publisher: MDPI AG
Date: 23-12-2023
DOI: 10.3390/IJMS24010252
Abstract: Bifidobacterium are prominent gut commensals that produce the short-chain fatty acid (SCFA) acetate, and they are often used as probiotics. Connections between the gut and the lung, termed the gut–lung axis, are regulated by the microbiome. The gut–lung axis is increasingly implicated in cigarette smoke-induced diseases, and cigarette smoke exposure has been associated with depletion of Bifidobacterium species. In this study, we assessed the impact of acetate-producing Bifidobacterium longum subsp. longum (WT) and a mutant strain with an impaired acetate production capacity (MUT) on cigarette smoke-induced inflammation. The mice were treated with WT or MUT B. longum subsp. longum and exposed to cigarette smoke for 8 weeks before assessments of lung inflammation, lung tissue gene expression and cecal SCFAs were performed. Both strains of B. longum subsp. longum reduced lung inflammation, inflammatory cytokine expression and adhesion factor expression and alleviated cigarette smoke-induced depletion in caecum butyrate. Thus, the probiotic administration of B. longum subsp. longum, irrespective of its acetate-producing capacity, alleviated cigarette smoke-induced inflammation and the depletion of cecal butyrate levels.
Publisher: MDPI AG
Date: 31-10-2021
DOI: 10.3390/APP112110205
Abstract: The genus Zingiber consists of about 85 species and many of these species are used as food, spices, and medicines. One of the species, Zingiber montanum (J. Koenig) Link ex A. Dietr. is native to Southeast Asia and has been extensively used as traditional medicines and food. The aim of this review was to collect and critically analyze the scientific information about the bioactive compounds and pharmacological activities of Z. montanum with focus on one of the main components, zerumbone (ZER). Various studies have reported the analysis of volatile constituents of the essential oils from Z. montanum. Similarly, many phenylbutanoids, flavonoids and terpenes were also isolated from rhizomes. These essential oils, extracts and compounds showed potent antimicrobial, anti-inflammatory and antioxidant activities among others. Zerumbone has been studied widely for its anticancer, anti-inflammatory, and other pharmacological activities. Future studies should focus on the exploration of various pharmacological activities of other compounds including phenylbutanoids and flavonoids. Bioassay guided isolation may result in the separation of other active components from the extracts. Z. montanum could be a promising source for the development of pharmaceutical products and functional foods.
Publisher: Cold Spring Harbor Laboratory
Date: 12-04-2023
DOI: 10.1101/2023.04.12.536514
Abstract: Primary air liquid interface (ALI) cultures of bronchial epithelial cells are used extensively to model airway responses. A recent advance is the development of conditional reprogramming that enhances proliferative capability. Several different media and protocols are utilized, yet even subtle differences may influence cellular responses. We compared the morphology and functional responses, including innate immune responses to rhinovirus infection in conditionally reprogrammed primary bronchial epithelial cells (pBECs) differentiated using two commonly used culture media. pBECs from healthy participants (n = 5) were CR using γ-irradiated 3T3 fibroblasts and Rho Kinase inhibitor. CRpBECs were differentiated at ALI in either PneumaCult™ (PN-ALI) or Bronchial Epithelial Growth Medium (BEGM)-based differentiation media (BEBM:DMEM, 50:50, Lonza™) - (AB-ALI) for 28 days. Transepithelial electrical resistance (TEER), immunofluorescence, histology, cilia activity, ion channel function, and expression of cell markers were analyzed. Viral load was assessed by RT-qPCR and anti-viral factors quantified by Legendplex following Rhinovirus-A1b (RVA1b) infection. CRpBECs differentiated in PneumaCult™ were smaller and had a lower TEER and cilia beat frequency (CBF) compared to BEGM media. PneumaCult™ media cultures exhibited significantly increased FOXJ1 expression, more ciliated cells with a larger active area, increased intracellular mucins, and increased calcium-activated chloride channel current. However, there were no significant changes in viral RNA or host antiviral responses. There are distinct structural and functional differences in CRpBECs cultured in the two commonly used ALI differentiation media. Such factors need to be taken into consideration when designing and comparing CRpBECs ALI experiments.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.BIOPHA.2018.08.101
Abstract: Tuberculosis (caused by Mycobacterium tuberculosis, Mtb) treatment involves multiple drug regimens for a prolonged period. However, the therapeutic benefit is often limited by poor patient compliance, subsequently leading to treatment failure and development of antibiotic resistance. Notably, oxidative stress is a crucial underlying factor that adversely influences the various treatment regimens in tuberculosis. Little information is available with advanced drug delivery systems that could be effectively utilized, in particular, for targeting the oxidative stress in tuberculosis. Thus, this presents an opportunity to review the utility of various available, controlled-release drug delivery systems (e.g., microspheres, liposomes, niosomes, solid lipid nanoparticles, dendrimers) that could be beneficial in tuberculosis treatments. This will help the biological and formulation scientists to pave a new path in formulating a treatment regimen for multi-drug resistant Mtb.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1038/MI.2011.55
Publisher: eLife Sciences Publications, Ltd
Date: 27-06-2019
DOI: 10.7554/ELIFE.42448
Abstract: Although respiratory syncytial virus (RSV) is responsible for more human deaths each year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and redox-sensitive dyes are used to define RSV’s impact on host mitochondria for the first time, delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and translocation towards the microtubule-organizing centre. These changes are concomitant with impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-induced lung inflammation. The results establish RSV’s unique ability to co-opt host cell mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time as a viable target for therapeutic intervention.
Publisher: European Respiratory Society (ERS)
Date: 25-10-2017
DOI: 10.1183/16000617.0040-2017
Abstract: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of developing nonsmall cell lung carcinoma, irrespective of their smoking history. Although the mechanisms behind this observation are not clear, established drivers of carcinogenesis in COPD include oxidative stress and sustained chronic inflammation. Mitochondria are critical in these two processes and recent evidence links increased oxidative stress in COPD patients to mitochondrial damage. We therefore postulate that mitochondrial damage in COPD patients leads to increased oxidative stress and chronic inflammation, thereby increasing the risk of carcinogenesis. The functional state of the mitochondrion is dependent on the balance between its biogenesis and degradation (mitophagy). Dysfunctional mitochondria are a source of oxidative stress and inflammasome activation. In COPD, there is impaired translocation of the ubiquitin-related degradation molecule Parkin following activation of the Pink1 mitophagy pathway, resulting in excessive dysfunctional mitochondria. We hypothesise that deranged pathways in mitochondrial biogenesis and mitophagy in COPD can account for the increased risk in carcinogenesis. To test this hypothesis, animal models exposed to cigarette smoke and developing emphysema and lung cancer should be developed. In the future, the use of mitochondria-based antioxidants should be studied as an adjunct with the aim of reducing the risk of COPD-associated cancer.
Publisher: The American Association of Immunologists
Date: 04-2009
DOI: 10.4049/JIMMUNOL.182.SUPP.133.44
Abstract: Rhinovirus (RV) infection is an important trigger of acute asthma and COPD. Study objectives were to characterise the response of PBMCs and CD8 lymphocytes when exposed to RV infected bronchial epithelial cells. Methods Human Calu3 cells were used as a model for bronchial epithelial cells and infected with RV-43 and RV-1B. PBMCs were obtained from healthy in iduals and separated by Ficoll-Paque centrifugation. CD8 lymphocytes were identified as CD3+, CD8+ by flow cytometry. PBMCs were exposed to infected Calu3 cells, cells exposed to UV inactive RV, PHA and TLR3 agonist PolyI:C. Response was measured by ELISA for release of interferon(IFN)-γ and TNF-α. CD8 activation with expression of perforin or proliferation measured by carboxyfluorescein succinimidyl ester assay. Results: Exposure of PBMCs to Calu3 cells infected with both RV led to significant release of IFN-γ and TNF-α, smaller release was seen in response to UV inactive RV. Exposure to PolyI:C also led to a similar release. CD8+ cells were found to be the primary source of IFN-γ release. CD8+ cells did not show an increase in perforin expression or evidence of proliferation. Conclusions exposure of PBMCs and CD8+ cells to an RV infected bronchial epithelium alone results in an innate immune response mediated by TLR3 without evidence of a CD8 adaptive immune response.
Publisher: Wiley
Date: 17-11-2017
DOI: 10.1002/PATH.4979
Abstract: Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c
Publisher: European Respiratory Society
Date: 09-2017
Publisher: Future Medicine Ltd
Date: 08-2021
Publisher: American Thoracic Society
Date: 05-2011
DOI: 10.1164/AJRCCM-CONFERENCE.2011.183.1_MEETINGABSTRACTS.A1008
Publisher: American Thoracic Society
Date: 05-2020
DOI: 10.1164/AJRCCM-CONFERENCE.2020.201.1_MEETINGABSTRACTS.A2634
Publisher: BMJ
Date: 06-03-2015
DOI: 10.1136/THORAXJNL-2014-206067
Abstract: Steroid-insensitive endotypes of asthma are an important clinical problem and effective therapies are required. They are associated with bacterial infection and non-eosinophilic inflammatory responses in the asthmatic lung. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma. However, whether the effects of macrolides are due to antimicrobial or anti-inflammatory mechanisms is not known. To determine and assess the efficacy of macrolide (ie, clarithromycin) and non-macrolide (ie, amoxicillin) antibiotic treatments in experimental models of infection-induced, severe, steroid-insensitive neutrophilic allergic airways disease (SSIAAD), compared with steroid-sensitive AAD and to delineate the antimicrobial and anti-inflammatory effects of macrolide therapy. We developed and used novel mouse models of Chlamydia and Haemophilus lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor α and interleukin 17 responses that induce SSIAAD. Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S12931-020-01445-6
Abstract: Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2 , TGFB1 , CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.TAAP.2013.05.009
Abstract: Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 23-06-2009
DOI: 10.1111/J.1751-0813.2009.00446.X
Abstract: To identify and gain an understanding of the influenza viruses circulating in wild birds in Australia. A total of 16,303 swabs and 3782 blood s les were collected and analysed for avian influenza (AI) viruses from 16,420 wild birds in Australia between July 2005 and June 2007. Anseriformes and Charadriiformes were primarily targeted. Cloacal, oropharyngeal and faecal (environmental) swabs were tested using polymerase chain reaction (PCR) for the AI type A matrix gene. Positive s les underwent virus culture and subtyping. Serum s les were analysed using a blocking enzyme-linked immunosorbent assay for influenza A virus nucleoprotein. No highly pathogenic AI viruses were identified. However, 164 PCR tests were positive for the AI type A matrix gene, 46 of which were identified to subtype. A total of five viruses were isolated, three of which had a corresponding positive PCR and subtype identification (H3N8, H4N6, H7N6). Low pathogenic AI H5 and/or H7 was present in wild birds in New South Wales, Tasmania, Victoria and Western Australia. Antibodies to influenza A were also detected in 15.0% of the birds s led. Although low pathogenic AI virus subtypes are currently circulating in Australia, their prevalence is low (1.0% positive PCR). Surveillance activities for AI in wild birds should be continued to provide further epidemiological information about circulating viruses and to identify any changes in subtype prevalence.
Publisher: European Respiratory Society
Date: 09-2016
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Bentham Science Publishers Ltd.
Date: 30-09-2019
DOI: 10.2174/1381612825666190717104547
Abstract: The incidence of diabetes has increased globally in recent years and figures of diabetic patients were estimated to rise up to 642 million by 2040. The disorder is accompanied with various complications if not managed at the early stages, and interlinked high mortality rate and morbidity with time. Different classes of drugs are available for the management of type 2 diabetes but were having certain limitations of their safety. Alphaglucosidase is a family of enzyme originated from the pancreas which plays a role in the anabolism of 80-90% of carbohydrate consumed into glucose. This glucose is absorbed into the blood and results in frank postprandial hyperglycemia and worsens the conditions of diabetic patients which precipitate complications. Inhibition of these enzymes helps to prevent postprandial hyperglycemia and the formation of glycated end products. Alphaglucosidase inhibitors are reported to be more important in adequate control of type 2, but marketed drugs have various side effects, such as poor patient compliance and also expensive. This proves the needs for other class of drugs with better efficacy, safety, patient compliance and economic. In this review, we have emphasized the recent advances in the field of new alpha-glucosidase inhibitors with improved safety and pharmacological profile.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.JRI.2014.09.051
Abstract: Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an immune response against invading pathogens. To achieve this, numerous changes must occur in the activity and function of maternal immune cells throughout the course of pregnancy. Respiratory viruses take advantage of these changes, altering the sensitive balance of maternal immunity, leaving the mother with increased susceptibility to viral infections and increased disease severity. Influenza virus is one of the most common respiratory virus infections during pregnancy, leading to an increased risk of ICU hospitalisations, pneumonia, acute respiratory distress syndrome and even death. Whilst much research has been performed to understand the changes that must take place in maternal immunity during pregnancy, considerable work is still needed to fully comprehend this tremendous feat. To date, few studies have focused on the alterations that occur in maternal immunity during respiratory virus infections. This review highlights the role of dendritic cells (DCs) and CD8 T cells during pregnancy, and the changes that occur in these antiviral cells following influenza virus infections.
Publisher: Public Library of Science (PLoS)
Date: 16-06-2016
Publisher: Wiley
Date: 29-01-2013
DOI: 10.1111/MEC.12144
Publisher: Public Library of Science (PLoS)
Date: 19-06-2012
Publisher: American Thoracic Society
Date: 12-2014
Publisher: Bentham Science Publishers Ltd.
Date: 11-01-2017
DOI: 10.2174/2211738505666170921125549
Abstract: Nifedipine is a potential therapeutic agent for the treatment of cardiovascular disturbances, although it suffers from short half-life (t1/2, 2 hr). To address the problem, we first prepared nifedipine loaded sustained release microsponges and then formulated tablets for effective clinical application and patient compliance. Preparations of microsponges were carried out using different compositions of nifedipine and polymer (1:1, 1:2 and 1:3 % molar ratio) using emulsion solvent diffusion technique. The microsponges with molar ratio 1:3 (formulation code: MF-3) found optimized as revealed by analyzing surface morphology, better powder flow properties (angle of repose 28.80 ± 0.9, Hausner ratio 1.15 ± 0.2, % compressibility 15.28 ± 0.5% and higher % drug content (80 ± 1.9 %). Different batches of tablets were then formulated incorporating MF-3 microsponges and different proportions (10-50 %) of microcrystalline cellulose and starch as additives. Among tablet formulations, batch composed of 48% of MF-3, 30% of MCC, 20 % of starch and 2 % of talc (TF-33), showed 92.73 ± 2.19 % drug release during 24 hr in vitro release study in comparison to other batches including commercial formulation which was found to be released completely in 20 hr. Further, stability analysis revealed good drug retention of loaded nifedipine as well as consistent in vitro release pattern over a period of 90 days at 40°C and 75% RH. The microsponge tablet delivery system was found to be superior concerning the therapeutic advantage as well as manufacturing feasibility of nifedipine.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.PHARMTHERA.2017.12.009
Abstract: Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology.
Publisher: Informa UK Limited
Date: 06-10-2021
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.BIOPHA.2018.09.138
Abstract: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by T cell-mediated self-destruction of insulin-secreting islet β cells. Management of T1DM is challenging and complicated especially with conventional medications. Gene therapy has emerged as one of the potential therapeutic alternatives to treat T1DM. This review primarily focuses on the current status and the future perspectives of gene therapy in the management of T1DM. A vast number of the studies which are reported on gene therapy for the management of T1DM are done in animal models and in preclinical studies. In addition, the safety of such therapies is yet to be established in humans. Currently, there are several gene level interventions that are being investigated, notably, overexpression of genes and proteins needed against T1DM, transplantation of cells that express the genes against T1DM, stem-cells mediated gene therapy, genetic vaccination, immunological precursor cell-mediated gene therapy and vectors. We searched the current literature through searchable online databases, journals and other library sources using relevant keywords and search parameters. Only relevant publications in English, between the years 2000 and 2018, with evidences and proper citations, were considered. The publications were then analyzed and segregated into several subtopics based on common words and content. A total of 126 studies were found suitable for this review. Generally, the pros and cons of each of the gene-based therapies have been discussed based on the results collected from the literature. However, there are certain interventions that require further detailed studies to ensure their effectiveness. We have also highlighted the future direction and perspectives in gene therapy, which, researchers could benefit from.
Publisher: MDPI AG
Date: 03-07-2022
DOI: 10.3390/PHARMACEUTICS14071401
Abstract: The present study aims to design, develop and characterize kNGR (Asn-Gly-Arg) peptide-conjugated lipid–polymer-based nanoparticles for the target-specific delivery of anticancer bioactive(s), i.e., Paclitaxel (PTX). The kNGR-PEG-DSPE conjugate was synthesized and characterized by using spectral analysis. The dual-targeted PLGA–lecithin–PEG core-shell nanoparticles (PLNs-kNGR-NPs) were synthesized using a modified nanoprecipitation process, and their physiological properties were determined. The results support that, compared to other NPs, PLNs-kNGR-NPs are highly cytotoxic, owing to higher apoptosis and intracellular uptake. The significance of rational nanoparticle design for synergistic treatment is shown by the higher tumor volume inhibition percentage rate (59.7%), compared to other designed formulations in Balb/c mice in the HT-1080 tumor-induced model. The overall results indicate that the PLNs-kNGR-NPs-based hybrid lipid–polymer nanoparticles present the highest therapeutic efficacy against solid tumor overexpressing the CD13 receptors.
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Wiley
Date: 18-01-2008
Publisher: Oxford University Press (OUP)
Date: 27-09-2019
Abstract: Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses however, their specific roles in the pathogenesis of COPD are unclear. Therefore, we investigated the roles of T and B lymphocytes and group 2 innate lymphoid cells (ILC2s) in airway inflammation and remodelling, and lung function in an experimental model of COPD using mice that specifically lack these cells (Rag1−/− and Rorafl/flIl7rCre [ILC2-deficient] mice). Wild-type (WT) C57BL/6 mice, Rag1−/−, and Rorafl/flIl7rCre mice were exposed to cigarette smoke (CS 12 cigarettes twice a day, 5 days a week) for up to 12 weeks, and airway inflammation, airway remodelling (collagen deposition and alveolar enlargement), and lung function were assessed. WT, Rag1−/−, and ILC2-deficient mice exposed to CS had similar levels of airway inflammation and impaired lung function. CS exposure increased small airway collagen deposition in WT mice. Rag1−/− normal air- and CS-exposed mice had significantly increased collagen deposition compared to similarly exposed WT mice, which was associated with increases in IL-33, IL-13, and ILC2 numbers. CS-exposed Rorafl/flIl7rCre mice were protected from emphysema, but had increased IL-33/IL-13 expression and collagen deposition compared to WT CS-exposed mice. T/B lymphocytes and ILC2s play roles in airway collagen deposition/fibrosis, but not inflammation, in experimental COPD. T/B lymphocytes and ILC2s play roles in airway fibrosis but not inflammation in a mouse model of experimental COPD.
Publisher: Elsevier BV
Date: 11-2014
Publisher: European Respiratory Society
Date: 15-09-2018
Publisher: Future Medicine Ltd
Date: 03-2021
Publisher: Wiley
Date: 12-02-2020
DOI: 10.1002/DDR.21648
Publisher: Public Library of Science (PLoS)
Date: 15-01-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
DOI: 10.1097/TA.0000000000001919
Abstract: Cell-free mitochondrial DNA (mtDNA) is proinflammatory and has been detected in high concentrations in trauma patients’ plasma. Deoxyribonuclease (DNAse) is the free plasma enzyme responsible for the digestion of extracellular DNA. The relationship between mtDNA and DNAse after major trauma is unknown. We hypothesized that DNAse activity would be elevated after injury and trauma surgery and would be associated with high concentrations of extracellular DNA. Two-year prospective study was performed on 103 consecutive trauma patients (male, 81% age, 38 years [interquartile range, 30–59 years] injury severity score, 18 [interquartile range, 12–26 years]) who underwent standardized major orthopedic trauma surgical interventions. Blood was collected at five perioperative time points (preoperative, postoperative, 7 hours, 24 hours, and 3 days postoperatively). Healthy control subjects (n = 20) were also s led. Cell-free mtDNA and nuclear DNA (nDNA) were measured using quantitative polymerase chain reaction. Deoxyribonuclease was also assayed in the same plasma s les. Increased levels of mtDNA (from preoperative 163 ± 86 ng/mL to 3 days 282 ± 201 ng/mL, p 0.0001) and nDNA (from preoperative 28 ± 20 ng/mL to 3 days 37 ± 27 ng/mL, p 0.05) were present in trauma patients at all perioperative time points compared with healthy controls (mtDNA: 4 ± 2 ng/mL nDNA: 10 ± 5 ng/mL). Deoxyribonuclease activity was lower in the trauma cohort (from preoperative 0.06 ± 0.04U/mL to 3 days 0.08 ± 0.04U/mL, p 0.0001) compared with healthy controls (DNAse: 0.17 ± 0.03U/mL). There was no correlation between DNAse and perioperative DNA concentrations. Elevated mtDNA (but not nDNA) correlated with the development of systemic inflammatory response syndrome (SIRS) ( p = 0.026) but not multiple organ failure. The significant perioperative elevation in plasma-free mtDNA concentration is associated with the development of SIRS. The fact that increased cell-free DNA concentrations present with significantly lower than healthy control DNAse activity suggests a potential therapeutic opportunity with DNAse administration to modulate postinjury severe SIRS. Prognostic/Epidemiological, level II.
Publisher: Public Library of Science (PLoS)
Date: 02-03-2012
Publisher: Future Medicine Ltd
Date: 10-2022
Publisher: European Respiratory Society (ERS)
Date: 02-2004
DOI: 10.1183/09031936.03.00081403
Abstract: A nonfatal pneumococcal lung infection model was required to investigate immune responses during recovery, and the interaction of other diseases subsequent to infection. A murine model of nonfatal pneumococcal lung infection was developed and the effect of genetic background on susceptibility was determined in BALB/c and C57BL/6 mice. Bacteria colonised the lungs and mice developed mild clinical illness with pathophysiology similar to human bronchopneumonia. Recovery was associated with immune cell influx, which cleared bacteria but induced tissue damage characteristic of pneumococcal bronchopneumonia. After clearance, immune cell populations returned to normal and tissues appeared less inflamed. Although bacterial exposure and clearance were similar, the extent of immune cell influx and tissue damage differed significantly. Larger numbers of neutrophils and lymphocytes entered lung tissue and the affected area was greater in BALB/c compared with C57BL/6 mice. An inflammatory basis for differences was determined with greater levels of phagocytosis and oxidative burst observed in BALB/c mice. C57BL/6 mice cleared the low inoculum with a reduced immune response however, C57BL/6 mice are more susceptible to larger inocula, which overwhelms the immune system. These different susceptibilities result from a greater inflammatory response in BALB/c compared with C57BL/6 mice.
Publisher: Public Library of Science (PLoS)
Date: 04-2015
Publisher: American Society for Clinical Investigation
Date: 16-06-2016
Publisher: American Thoracic Society
Date: 04-2009
DOI: 10.1164/AJRCCM-CONFERENCE.2009.179.1_MEETINGABSTRACTS.A3729
Publisher: BMJ
Date: 10-06-2016
Publisher: European Respiratory Society (ERS)
Date: 19-05-2020
DOI: 10.1183/13993003.02320-2019
Abstract: Chronic respiratory diseases are highly prevalent worldwide and will continue to rise in the foreseeable future. Despite intensive efforts over the recent decades, the development of novel and effective therapeutic approaches has been slow. There is however new and increasing evidence that communities of microorganisms in our body, the human microbiome, are crucially involved in the development and progression of chronic respiratory diseases. Understanding the detailed mechanisms underlying this cross-talk between host and microbiota is critical for development of microbiome- or host-targeted therapeutics and prevention strategies. Here we review and discuss the most recent knowledge on the continuous reciprocal interaction between the host and microbes in health and respiratory disease. Furthermore, we highlight promising developments in microbiome-based therapies and discuss the need to employ more holistic approaches of restoring both the pulmonary niche and the microbial community.
Publisher: Informa UK Limited
Date: 11-05-2019
DOI: 10.1080/14728222.2019.1615884
Abstract: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation. Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer. Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.
Publisher: AME Publishing Company
Date: 10-2019
Publisher: The American Association of Immunologists
Date: 05-2015
DOI: 10.4049/JIMMUNOL.194.SUPP.191.10
Abstract: BACKGROUND: Severe, steroid-insensitive (SSI) asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is h ered by a lack of understanding of the mechanisms that promote disease. SSI asthma is associated with respiratory infections and non-eosinophilic endotypes of disease, including neutrophilic asthma. OBJECTIVES: To develop and use mouse models of SSI neutrophilic asthma to investigate pathogenic mechanisms involving microRNA (miR)-21, phosphoinositide-3-kinase (PI3K) and histone deacetylase (HDAC)2 in order to identify new therapeutic approaches. METHODS: Novel mouse models of respiratory infection and ovalbumin-induced, SSI neutrophilic allergic airway disease (SSIAAD) in BALB/c mice were developed. The roles of infection-induced miR-21 expression and PI3K-dependent signalling in the lung were examined using a specific miR-21 inhibitor (antagomir-21) and the pan-PI3K inhibitor LY294002. RESULTS: Infection induced a miR-21-dependent, PI3K-mediated signalling pathway that decreased nuclear HDAC2 levels and promoted steroid-insensitive neutrophilic inflammation and airway hyper-responsiveness (AHR) in AAD. Inhibition of miR-21 or PI3K suppressed nuclear pAkt levels and restored HDAC2 levels and steroid sensitivity. CONCLUSIONS: We have identified a novel role for a miR-21/PI3K/HDAC2 signalling axis in SSIAAD. Our data highlights miR-21 as a novel target for treating this form of asthma.
Publisher: Elsevier BV
Date: 10-2014
Publisher: The American Association of Immunologists
Date: 15-10-2013
Abstract: The induction of regulatory T cells (Tregs) to suppress aberrant inflammation and immunity has potential as a therapeutic strategy for asthma. Recently, we identified key immunoregulatory components of Streptococcus pneumoniae, type 3 polysaccharide and pneumolysoid (T+P), which suppress allergic airways disease (AAD) in mouse models of asthma. To elucidate the mechanisms of suppression, we have now performed a thorough examination of the role of Tregs. BALB/c mice were sensitized to OVA (day 0) i.p. and challenged intranasal (12–15 d later) to induce AAD. T+P was administered intratracheally at the time of sensitization in three doses (0, 12, and 24 h). T+P treatment induced an early (36 h–4 d) expansion of Tregs in the mediastinal lymph nodes, and later (12–16 d) increases in these cells in the lungs, compared with untreated allergic controls. Anti-CD25 treatment showed that Treg-priming events involving CD25, CCR7, IL-2, and TGF-β were required for the suppression of AAD. During AAD, T+P-induced Tregs in the lungs displayed a highly suppressive phenotype and had an increased functional capacity. T+P also blocked the induction of IL-6 to prevent the Th17 response, attenuated the expression of the costimulatory molecule CD86 on myeloid dendritic cells (DCs), and reduced the number of DCs carrying OVA in the lung and mediastinal lymph nodes. Therefore, bacterial components (T+P) drive the differentiation of highly suppressive Tregs, which suppress the Th2 response, prevent the Th17 response and disable the DC response resulting in the effective suppression of AAD.
Publisher: American Thoracic Society
Date: 05-2020
DOI: 10.1164/AJRCCM-CONFERENCE.2020.201.1_MEETINGABSTRACTS.A2543
Publisher: Elsevier BV
Date: 12-1992
DOI: 10.1016/0005-2736(92)90391-X
Abstract: Dimyristoylphosphatidylinositol (DMPI) has been synthesized with the appropriate natural stereochemistry and labelled with deuterium at specific sites in the D-myo-inositol headgroup. 2H-NMR spectroscopy of DMPI in its lamellar phase at a molar ratio of water-to-lipid RW/L of 129 and at 70 degrees C reveals quadrupolar splittings delta v of 3.83 and 2.17 kHz, respectively, for the five axially oriented C-D bonds and the single equatorially oriented C-D bond of the D-myo-inositol headgroup. Between RW/L ratios of 129 and 210 and between 30 degrees C and 80 degrees C the value of the ratio of these splittings delta nu ax/delta nu eq varies significantly (between 1.17 and 4.38). If it is assumed that, at a particular temperature, there is a single preferred orientation of the inositol headgroup, and that motion of the DPMI molecule establishes axial symmetry with respect to the bilayer normal then the ratio of these quadrupolar splittings can be used to impose constraints on that orientation. For ex le, the data are inconsistent with a situation in which the inositol ring lies parallel to the membrane surface and are difficult to reconcile with an arrangement where the inositol ring lies perpendicular to the surface. Computational modelling identifies four possible 'tilted' orientations, all of which are consistent with the data, and two of these allow good intramolecular hydrogen bonds to be formed. In one there is hydrogen bonding between the inositol C2-OH and the phosphate pro-R oxygen. This is close to the conformation previously identified as being dominant in DMSO solution (Bushby, R.J., Byard, S.J., Hansbro, P.M. and Reid, D.G. (1990) Biochim. Biophys. Acta 1044, 231-236).
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 23-03-2019
DOI: 10.1007/S11892-019-1144-3
Abstract: Type 1 diabetes (T1D) occurs when there is destruction of beta cells within the islets of Langerhans in the pancreas due to autoimmunity. It is considered a complex disease, and different complications can surface and worsen the condition if T1D is not managed well. Since it is an incurable disease, numerous treatments and therapies have been postulated in order to control T1D by balancing hyperglycemia control while minimizing hypoglycemic episodes. The purpose of this review is to primarily look into the current state of the available immunological therapies and their advantages for the treatment of T1D. Over the years, immunological therapy has become the center of attraction to treat T1D. Immunomodulatory approaches on non-antigens involving agents such as cyclosporine A, mycophenolate mofetil, anti-CD20, cytotoxic T cells, anti-TNF, anti-CD3, and anti-thymocyte globulin as well as immunomodulative approaches on antigens such as insulin, glutamic acid decarboxylase, and heat shock protein 60 have been studied. Aside from these two approaches, studies and trials have also been conducted on regulatory T cells, dendritic cells, interleukin 2, interleukin 4, M2 macrophages, and rapamycin/interleukin 2 combination therapy to test their effects on patients with T1D. Many of these agents have successfully suppressed T1D in non-obese diabetic (NOD) mice and in human trials. However, some have shown negative results. To date, the insights into the management of the immune system have been increasing rapidly to search for potential therapies and treatments for T1D. Nevertheless, some of the challenges are still inevitable. A lot of work and effort need to be put into the investigation on T1D through immunological therapy, particularly to reduce complications to improve and enhance clinical outcomes.
Publisher: European Respiratory Society (ERS)
Date: 13-06-2019
DOI: 10.1183/13993003.00174-2018
Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis. Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD. IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4 + T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient ( Il22 −/− ) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22 −/− mice. Il22 −/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance. These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.
Publisher: Wiley
Date: 17-06-2020
Publisher: Bentham Science Publishers Ltd.
Date: 04-2021
DOI: 10.2174/0929867327999200819145327
Abstract: Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.
Publisher: American Thoracic Society
Date: 08-2017
Publisher: American Thoracic Society
Date: 05-2015
Publisher: Hindawi Limited
Date: 11-10-2018
DOI: 10.1155/2018/7695364
Abstract: Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis , is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S -oxidation) and pathogen (catalase eroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD + ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host’s OS response.
Publisher: American Thoracic Society
Date: 06-2011
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Elsevier BV
Date: 09-2006
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 11-2014
Publisher: Frontiers Media SA
Date: 14-11-2016
Publisher: Springer Science and Business Media LLC
Date: 20-03-2023
DOI: 10.1186/S12950-023-00333-2
Abstract: The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support. The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/462934
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JACI.2018.04.037
Abstract: Both obesity and high dietary fat intake activate the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers. Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1β protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1β release was measured (ELISA). In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1β protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1β when challenged with a combination of palmitic acid and LPS or TNF-α. The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.
Publisher: The American Association of Immunologists
Date: 10-2010
Abstract: Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ–producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target.
Publisher: Public Library of Science (PLoS)
Date: 21-02-2019
Publisher: Elsevier BV
Date: 05-1990
DOI: 10.1016/0005-2760(90)90307-J
Abstract: The temperature dependence of the 1H-NMR spectrum of phosphatidylinositol (PI) in d6-dimethylsulphoxide (DMSO) shows that the hydroxy groups at C2 and at C6 of the inositol ring are internally hydrogen-bonded. This probably implies a trans/gauche conformation for the phosphate/inositol linkage. The presence of a trans phosphate-alkyl-oxygen bond is confirmed by 31P-NMR studies. If the conformation of PI in membranes is the same as that in DMSO solution, this implies that the inositol ring points out into the aqueous phase with its C1/C4 axis almost perpendicular to the membrane surface. Progress is also reported in attempts to characterise headgroup orientation and dynamics by 2H-NMR using deuterated synthetic PI, prepared by the route devised by Ward, J.G. and Young, R.C. (Tetrahedron Lett. 29 (1988) 6013-6016).
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Publisher: Oxford University Press (OUP)
Date: 04-2012
DOI: 10.1189/JLB.0711357
Abstract: Asthma is recognized as a heterogeneous disorder, although in most patients, the clinical manifestations are effectively managed with established combination therapies. However, 5–10% of asthmatics have severe asthma, which does not respond to treatment, and these patients account for & % of asthma-related healthcare costs. New investigations into the pathogenesis of glucocorticoid resistance in severe asthma indicate that pulmonary macrophages may play central roles in promoting airway inflammation, particularly in asthma that is resistant to steroid therapy. Importantly, factors that are linked to the activation of pulmonary macrophages may contribute to glucocorticoid resistance and severe asthma. Here, we review recent advances in understanding the roles of pulmonary macrophages in the mechanisms of glucocorticoid resistance and the pathogenesis of severe asthma. We discuss the role of macrophage phenotype, infection, IFN-γ, LPS, associated signaling pathways, TNF-α, MIF, and other macrophage-associated factors. Understanding the pathogenesis of steroid-resistant severe asthma will contribute to the identification of optimal therapeutic strategies for the effective management of the disease.
Publisher: The American Association of Immunologists
Date: 15-01-2008
DOI: 10.4049/JIMMUNOL.180.2.1199
Abstract: The eosinophil is a central effector cell in allergic asthma. Differentiation and function of eosinophils are regulated by the CD4 Th2 cytokines IL-3, IL-5, and GM-CSF, which all signal through a common β receptor subunit (βc). Recent therapeutic approaches targeting IL-5 alone have not ablated tissue accumulation of eosinophils and have had limited effects on disease progression, suggesting important roles for IL-3 and GM-CSF. By using a mouse model of allergic airways inflammation, we show that allergen-induced expansion and accumulation of eosinophils in the lung are abolished in βc-deficient (βc−/−) mice. Moreover, βc deficiency resulted in inhibition of hallmark features of asthma, including airways hypersensitivity, mucus hypersecretion, and production of Ag-specific IgE. Surprisingly, we also identified a critical role for this receptor in regulating type 2 immunity. Th2 cells in the lung of allergen-challenged βc−/− mice were limited in their ability to proliferate, produce cytokines, and migrate to effector sites, which was attributed to reduced numbers of myeloid dendritic cells in the lung compartment. Thus, the βc plays a critical role in allergen-induced eosinophil expansion and infiltration and is pivotal in regulating molecules that promote both early and late phases of allergic inflammation, representing a novel target for therapy.
Publisher: Bentham Science Publishers Ltd.
Date: 24-01-2018
DOI: 10.2174/2211738505666170808094635
Abstract: Vesicular systems like nanotechnology and liposomes are gaining tremendous attention lately in the field of respiratory diseases. These formulations enhance bioavailability of the drug candidate, which could be achieved through a novel drug delivery mechanism. Moreover, the therapeutic potential achieved through these systems is highly controllable over long durations of time providing better efficacy and patient compliance. The objective of this paper is to review the recent literature on vesicular drug delivery systems containing curcumin. We have collated and summarized various recent attempts made to develop different controlled release drug delivery systems containing curcumin which would be of great interest for herbal, formulation and biological scientists. There are several vesicular nanotechnological techniques involving curcumin which have been studied recently, targeting pulmonary diseases. Different vesicular systems containing curcumin are being studied for their therapeutic potential in different respiratory diseases. There has been a renewed interest in formulations containing curcumin recently, primarily owing to the broad spectrum therapeutic potential of this miracle substance. Various types of formulations, containing curcumin, targeting different bodily systems have recently emerged and, nevertheless, the search for newer frontiers with this drug goes on. This mini review, in this direction, tries to highlight the key research interventions employing vesicular systems of drug delivery with curcumin.
Publisher: Wiley
Date: 29-04-2023
DOI: 10.1002/MED.21956
Abstract: The global burden of respiratory diseases is enormous, with many millions of people suffering and dying prematurely every year. The global COVID‐19 pandemic witnessed recently, along with increased air pollution and wildfire events, increases the urgency of identifying the most effective therapeutic measures to combat these diseases even further. Despite increasing expenditure and extensive collaborative efforts to identify and develop the most effective and safe treatments, the failure rates of drugs evaluated in human clinical trials are high. To reverse these trends and minimize the cost of drug development, ineffective drug candidates must be eliminated as early as possible by employing new, efficient, and accurate preclinical screening approaches. Animal models have been the mainstay of pulmonary research as they recapitulate the complex physiological processes, Multiorgan interplay, disease phenotypes of disease, and the pharmacokinetic behavior of drugs. Recently, the use of advanced culture technologies such as organoids and lung‐on‐a‐chip models has gained increasing attention because of their potential to reproduce human diseased states and physiology, with clinically relevant responses to drugs and toxins. This review provides an overview of different animal models for studying respiratory diseases and evaluating drugs. We also highlight recent progress in cell culture technologies to advance integrated models and discuss current challenges and present future perspectives.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2020
Publisher: Springer Science and Business Media LLC
Date: 18-11-2020
DOI: 10.1038/S41467-020-19701-0
Abstract: Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death globally, and manifests as a progressive inflammatory lung disease with no curative treatment. The lung microbiome contributes to COPD progression, but the function of the gut microbiome remains unclear. Here we examine the faecal microbiome and metabolome of COPD patients and healthy controls, finding 146 bacterial species differing between the two groups. Several species, including Streptococcus sp000187445 , Streptococcus vestibularis and multiple members of the family Lachnospiraceae , also correlate with reduced lung function. Untargeted metabolomics identifies a COPD signature comprising 46% lipid, 20% xenobiotic and 20% amino acid related metabolites. Furthermore, we describe a disease-associated network connecting Streptococcus parasanguinis_B with COPD-associated metabolites, including N-acetylglutamate and its analogue N-carbamoylglutamate. While correlative, our results suggest that the faecal microbiome and metabolome of COPD patients are distinct from those of healthy in iduals, and may thus aid in the search for biomarkers for COPD.
Publisher: Informa UK Limited
Date: 07-07-2020
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 28-06-2017
DOI: 10.1111/IMR.12549
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 13-11-2006
DOI: 10.1111/J.1365-2222.2006.02595.X
Abstract: IL-25, a novel member of the IL-17 cytokine family, promotes CD4+ T-helper 2 lymphocyte-like (Th type-2) inflammatory responses in the lung. Although IL-25 up-regulates IL-13 in the lung, the contribution of this and other type 2 cytokine signalling pathways to the induction and persistence of airways hyper-reactivity (AHR) and allergic inflammation are unclear. To determine the downstream factors employed by IL-25 to induce Th type-2 pulmonary inflammation and AHR. IL-25 was delivered to the airways of BALB/c mice by intra-tracheal (i.t.) instillation and AHR and Th type-2 inflammatory responses were characterized in wild type (WT) and Th type-2-cytokine and -signalling pathway-deficient (-/-) mice. IL-25 treatment resulted in AHR, eosinophilic inflammation, mucus hypersecretion and a progressive increase in the production of Th type-2 cytokines in the lungs. Levels of arginase-I (arg-I) and eotaxin were also elevated by IL-25 treatment. A significant reduction in AHR, and attenuation of mucus production was observed in IL-25-treated IL-13-/-, IL-4 receptor alpha (IL-4Ralpha-/-)- and signal-transducer-and-activator-of-transcription-factor-6 (STAT6-/-)-deficient mice. AHR was also inhibited in IL-4(-/-)- and IL-5/eotaxin(1)(-/-)- deficient mice treated with IL-25, however, mucus hypersecretion was not completely ablated. IL-25 promoted Th type-2 responses by directly acting on naïve T cells. IL-25 potently (single dose) induces sustained AHR and acute pulmonary inflammation with eosinophilia. IL-25-induced AHR is dependent on the production of Th type-2 cytokines, and removal of IL-13 and its signal transduction pathway prevents IL-25-induced airways inflammation and AHR. IL-25 potently induces inflammatory cascades that may exacerbate allergic airways inflammation by promoting Th type-2 cytokine responses in conjunction with the up-regulation of factors (eotaxin and arg-I) that can lify inflammation associated with allergic disorders. Dysregulation in IL-25 production may predispose to features of allergic airways disease.
Publisher: Springer Science and Business Media LLC
Date: 09-1998
Abstract: Specific mgi mutations in the alpha, beta or gamma subunits of the mitochondrial F1-ATPase have previously been found to suppress rho0 lethality in the petite-negative yeast Kluyveromyces lactis. To determine whether the suppressive activity of the altered F1 is dependent on the F0 sector of ATP synthase, we isolated and disrupted the genes KlATP4, 5 and 7, the three nuclear genes encoding subunits b, OSCP and d. Strains disrupted for any one, or all three of these genes are respiration deficient and have reduced viability. However a strain devoid of the three nuclear genes is still unable to lose mitochondrial DNA, whereas a mgi mutant with the three genes inactivated remains petite-positive. In the latter case, rho0 mutants can be isolated, upon treatment with ethidium bromide, that lack six major F0 subunits, namely the nucleus-encoded subunits b, OSCP and d, and the mitochondrially encoded Atp6, 8 and 9p. Production of rho0 mutants indicates that an F1-complex carrying a mgi mutation can assemble in the absence of F0 subunits and that suppression of rho0 lethality is an intrinsic property of the altered F1 particle.
Publisher: Cambridge University Press (CUP)
Date: 14-02-2012
Publisher: Wiley
Date: 15-04-2020
Publisher: Elsevier BV
Date: 12-2019
Publisher: Wiley
Date: 28-06-2017
DOI: 10.1111/IMR.12543
Abstract: Severe, steroid-resistant asthma is clinically and economically important since affected in iduals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been h ered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.
Publisher: Royal Zoological Society of New South Wales
Date: 2020
DOI: 10.7882/AZ.2019.026
Abstract: Technologies for remotely observing animal movements have advanced rapidly in the past decade. In recent years, Australia has invested in an Integrated Marine Ocean Tracking (IMOS) system, a land ecosystem observatory (TERN), and an Australian Acoustic Observatory (A2O), but has not established movement tracking systems for in idual terrestrial animals across land and along coastlines. Here, we make the case that the Motus Wildlife Tracking System, an open-source, rapidly expanding cooperative automated radio-tracking global network (Motus, motus.org ) provides an unprecedented opportunity to build an affordable and proven infrastructure that will boost wildlife biology research and connect Australian researchers domestically and with international wildlife research. We briefly describe the system conceptually and technologically, then present the unique strengths of Motus, how Motus can complement and expand existing and emerging animal tracking systems, and how the Motus framework provides a much-needed central repository and impetus for archiving and sharing animal telemetry data. We propose ways to overcome the unique challenges posed by Australia’s ecological attributes and the size of its scientific community. Open source, inherently cooperative and flexible, Motus provides a unique opportunity to leverage in idual research effort into a larger collaborative achievement, thereby expanding the scale and scope of in idual projects, while maximising the outcomes of scant research and conservation funding.
Publisher: Research Square Platform LLC
Date: 09-2020
DOI: 10.21203/RS.3.RS-57848/V2
Abstract: The authors have withdrawn this preprint due to erroneous posting.
Publisher: Research Square Platform LLC
Date: 27-08-2020
DOI: 10.21203/RS.3.RS-57848/V1
Abstract: Toll-like receptor (TLR)7 is known for eliciting immunity against single-stranded RNA viruses. TLR7 was increased in both human and cigarette smoke (CS)-induced experimental chronic obstructive pulmonary disease (COPD). Severity of CS-induced emphysema and COPD was reduced in TLR7-deficient mice whilst inhalation of imiquimod (TLR7-agonist) induced emphysema in naïve mice. Imiquimod-induced emphysema was reduced in mice treated with mast cell stabilizer cromolyn or deficient in mast cell protease-6. Therapeutic treatment with anti-TLR7 monoclonal antibody suppressed CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells. We demonstrate an unexpected role for TLR7 in mediating emphysema and COPD through mast cell activity.
Publisher: Elsevier BV
Date: 03-2004
Publisher: AMPCo
Date: 30-08-2020
DOI: 10.5694/MJA2.50754
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.BBI.2014.10.014
Abstract: The immune and nociceptive systems are shaped during the neonatal period where they undergo fine-tuning and maturation. Painful experiences during this sensitive period of development are known to produce long-lasting effects on the immune and nociceptive responses. It is less clear, however, whether inflammatory pain responses are primed by neonatal exposure to mild immunological stimuli, such as with lipopolysaccharide (LPS). Here, we examine the impact of neonatal LPS exposure on inflammatory pain responses, peripheral and hippoc al interleukin-1β (IL-1β), as well as mast cell number and degranulation in preadolescent and adult rats. Wistar rats were injected with LPS (0.05mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 22 and 80-97. At both time-points, and one-hour after formalin injection, blood and hippoc us were collected for measuring circulating and central IL-1β levels using ELISA and Western blot, respectively. Paw tissue was also isolated to assess mast cell number and degree of degranulation using Toluidine Blue staining. Behavioural analyses indicate that at PND 22, LPS-challenged rats displayed enhanced flinching (p<.01) and licking (p<.01) in response to formalin injection. At PNDs 80-97, LPS-challenged rats exhibited increased flinching (p<.05), an effect observed in males only. Furthermore, neonatal LPS exposure enhanced circulating IL-1β and mast cell degranulation in preadolescent but not adult rats following formalin injection. Hippoc al IL-1β levels were increased in LPS-treated adult but not preadolescent rats in response to formalin injection. These data suggest neonatal LPS exposure produces developmentally regulated changes in formalin-induced behavioural responses, peripheral and central IL-1β levels, as well as mast cell degranulation following noxious stimulation later in life. These findings highlight the importance of immune activation during the neonatal period in shaping immune response and pain sensitivity later in life. This is of clinical relevance given the high prevalence of bacterial infection during the neonatal period, particularly in the vulnerable population of preterm infants admitted to neonatal intensive care units.
Publisher: Bentham Science Publishers Ltd.
Date: 08-2011
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.COPH.2019.06.003
Abstract: Asthma is a common, heterogeneous and serious disease with high prevalence globally. Poorly controlled, steroid-resistant asthma is particularly important as there are no effective therapies and it exerts substantial healthcare and societal burden. The role of microbiomes, particularly in chronic diseases has generated considerable interest in recent times. Existing evidence clearly demonstrates an association between asthma initiation and the microbiome, both respiratory and gastro-intestinal, although its' roles are poorly understood when assessing the asthma progression or heterogeneity (i.e. phenotypes/endotypes) across different geographical locations. Moreover, modulating microbiomes could be preventive and/or therapeutic in patients with asthma warrants urgent attention. Here, we review recent advances in assessing the role of microbiomes in asthma and present the challenges associated with the potential therapeutic utility of modifying microbiomes in management.
Publisher: Wiley
Date: 25-03-2017
DOI: 10.1111/RESP.13032
Publisher: American Thoracic Society
Date: 09-2017
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.COLSURFB.2018.08.027
Abstract: Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the anti-inflammatory activity of curcumin along with its molecular mechanism involving different signalling pathways. However, the physicochemical and biological properties such as poor solubility and rapid metabolism of curcumin have led to low bioavailability and hence limits its application. Current therapies for asthma such as bronchodilators and inhaled corticosteroids (ICS) are aimed at controlling disease symptoms and prevent asthma exacerbation. However, this approach requires lifetime therapy and is associated with a constellation of side effects. This creates a clear unmet medical need and there is an urgent demand for new and more-effective treatments. The present study is aimed to formulate liposomes containing curcumin and evaluate for its anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation on BCi-NS1.1 cell line. Curcumin and salbutamol liposomes were formulated using lipid hydration method. The prepared liposomes were characterized in terms of particle size, zeta potential, encapsulation efficiency and in-vitro release profile. The liposomes were tested on BCI-NS1.1 cell line to evaluate its anti-inflammatory properties. The various pro-inflammatory markers studied were Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1β (IL-1β) and Tumour Necrosis Factor-a (TNF-a). Additionally, molecular mechanics simulations were used to elucidate the positioning, energy minimization, and aqueous dispersion of the liposomal architecture involving lecithin and curcumin. The prepared curcumin formulation showed an average size and zeta potential of 271.3 ± 3.06 nm and -61.0 mV, respectively. The drug encapsulation efficiency of liposomal curcumin is 81.1%. Both curcumin-loaded liposomes formulation (1 μg/mL, 5 μg/mL) resulted in significant (p < 0.05) reduction in the level of pro-inflammatory marker expression such as IL-6, IL-8, IL-1β and TNF-a compared to positive control group. Liposomal curcumin with the dose of 1 μg/mL reduced the inflammatory markers more effectively compared to that of 5 μg/mL. Liposomal curcumin could be a promising intervention for asthma therapy showing their efficacy in suppressing the important pro-inflammatory markers involved in the pathogenesis of asthma.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.AJPATH.2018.03.016
Abstract: Inflammatory bowel disease (IBD) is associated with several immune-mediated extraintestinal manifestations. More than half of all IBD patients have some form of respiratory pathology, most commonly neutrophil-mediated diseases, such as bronchiectasis and chronic bronchitis. Using murine models of colitis, we aimed to identify the immune mechanisms driving pulmonary manifestations of IBD. We found increased neutrophil numbers in lung tissue associated with the pulmonary vasculature in both trinitrobenzenesulfonic acid- and dextran sulfate sodium-induced models of colitis. Analysis of systemic inflammation identified that neutrophilia was associated with bacteremia and pyrexia in animal models of colitis. We further identified IL-6 as a systemic mediator of neutrophil recruitment from the bone marrow of dextran sulfate sodium animals. Functional inhibition of IL-6 led to reduced systemic and pulmonary neutrophilia, but it did not attenuate established colitis pathology. These data suggest that systemic bacteremia and pyrexia drive IL-6 secretion, which is a critical driver for pulmonary manifestation of IBD. Targeting IL-6 may reduce neutrophil-associated extraintestinal manifestations in IBD patients.
Publisher: Elsevier BV
Date: 03-2000
DOI: 10.1016/S0167-4838(00)00003-0
Abstract: Characterisation of 35 Kluyveromyces lactis strains lacking mitochondrial DNA has shown that mutations suppressing rho(0)-lethality are limited to the ATP1, 2 and 3 genes coding for the alpha-, beta- and gamma- subunits of mitochondrial F(1)-ATPase. All atp mutations reduce growth on glucose and three alleles, atp1-2, 1-3 and atp3-1, produce a respiratory deficient phenotype that indicates a drop in efficiency of the F(1)F(0)-ATP synthase complex. ATPase activity is needed for suppression as a double mutant containing an atp allele, together with a mutation abolishing catalytic activity, does not suppress rho(0)-lethality. Positioning of the seven amino acids subject to mutation on the bovine F(1)-ATPase structure shows that two residues are found in a membrane proximal region while five amino acids occur at a region suggested to be a molecular bearing. The intriguing juxtaposition of mutable amino acids to other residues subject to change suggests that mutations affect subunit interactions and alter the properties of F(1) in a manner yet to be determined. An explanation for suppressor activity of atp mutations is discussed in the context of a possible role for F(1)-ATPase in the maintenance of mitochondrial inner membrane potential.
Publisher: American Society for Clinical Investigation
Date: 08-12-2016
Publisher: Wiley
Date: 05-07-2021
DOI: 10.1111/RESP.14111
Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. We employed quantitative label‐based proteomics to map the changes in the lung tissue proteome of cigarette smoke‐induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4‐ and 6‐week time points, compared to age‐matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy s les. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA‐binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.BIOCEL.2017.05.003
Abstract: Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.
Publisher: Elsevier
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NI.2913
Publisher: Bentham Science Publishers Ltd.
Date: 08-2010
DOI: 10.2174/138945010791591412
Abstract: Glucocorticoids are the mainstay of asthma management and effectively treat acute exacerbations of asthma. However, a small subset of asthmatics, usually with severe asthma, respond poorly even to systemic administration of high-dose glucocorticoids and this condition is termed "steroid-resistant asthma". This cohort, although small, accounts for approximately 50% of total health care cost for asthma. New investigations into the mechanisms of glucocorticoid action have broadened and deepened our understanding of glucocorticoid resistance. Here we review the importance and characteristics of steroid resistant asthma, the mechanisms that mediate the function of glucocorticoids and that lead to the development of this disease and potential therapies to reverse resistance to treatment. Cellular and molecular factors, receptors and complex signalling pathways have all been implicated. Indeed, based on molecular biological studies, excessive activation of intracellular transcription factors, impaired histone deacetylase, and epigenetic (such as miR-18 and miR-124a) as well as other factors (e.g. vitamin D, P-glycoprotein 170, and macrophage migration inhibitory factor and T helper 17 cells and factors related to innate immunity (such as IFN-gamma and LPS)) may result in glucocorticoid resistance. A thorough understanding of the pathogenesis of steroid resistant asthma will help to develop more efficacious agents for the treatment of the disease.
Publisher: Wiley
Date: 03-2017
DOI: 10.1038/CTI.2017.6
Publisher: Elsevier BV
Date: 04-1994
Abstract: The ability of the novel D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3] analogues, L-chiro-inositol 1,4,6-trisphosphate [L-chr Ins(1,4,6)P3] and the corresponding trisphosphorothioate compound [L-chr Ins(1,4,6)PS3] to inhibit soluble inositol (1,4,5)P3/(1,3,4,5)P4-polyphosphate 5-phosphatase, potently and selectively, has been investigated. L-chr Ins(1,4,6)P3 competitively inhibited 5-phosphate specific dephosphorylation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] with apparent Ki values of 6.35 and 1.76 microM, respectively. L-chr Ins(1,4,6)PS3 competitively inhibited hydrolysis of Ins(1,4,5)P3 and noncompetitively inhibited dephosphorylation of Ins(1,3,4,5)P4 with apparent Ki values of 0.67 and 0.44 microM, respectively. L-chr Ins(1,4,6)PS3 did not affect Ins(1,4,5)P3 3-kinase activity. In the present investigation L-chr Ins(1,4,6)P3 and L-chr Ins(1,4,6)PS3 have been shown to be the most potent and selective inhibitors of inositol polyphosphate metabolism yet described.
Publisher: Bentham Science Publishers Ltd.
Date: 12-12-2020
DOI: 10.2174/1381612826999201116161143
Abstract: Cell Signaling pathways form an integral part of our existence that allows the cells to comprehend a stimulus and respond back. Such reactions to external cues from the environment are required and are essential to regulate the normal functioning of our body. Abnormalities in the system arise when there are errors developed in these signals, resulting in a complication or a disease. Presently, respiratory diseases contribute to being the third leading cause of morbidity worldwide. According to the current statistics, over 339 million people are asthmatic, 65 million are suffering from COPD, 2.3 million are lung cancer patients and 10 million are tuberculosis patients. This toll of statistics with chronic respiratory diseases leaves a heavy burden on society and the nation& #039 s annual health expenditure. Hence, a better understanding of the processes governing these cellular pathways will enable us to treat and manage these deadly respiratory diseases effectively. Moreover, it is important to comprehend the synergy and interplay of the cellular signaling pathways in respiratory diseases, which will enable us to explore and develop suitable strategies for targeted drug delivery. This review, in particular, focuses on the major respiratory diseases and further provides an in-depth discussion on the various cell signaling pathways that are involved in the pathophysiology of respiratory diseases. Moreover, the review also analyses the defining concepts about advanced nano-drug delivery systems involving various nanocarriers and propose newer prospects to minimize the current challenges faced by researchers and formulation scientists.
Publisher: Wiley
Date: 11-2017
Publisher: Elsevier
Date: 2020
Publisher: Wiley
Date: 15-09-2023
DOI: 10.1111/RESP.14593
Publisher: MDPI AG
Date: 02-10-2022
Abstract: Pericytes (PCs), as a central component of the neurovascular unit, contribute to the regenerative potential of the central nervous system (CNS) and peripheral nervous system (PNS) by virtue of their role in blood flow regulation, angiogenesis, maintenance of the BBB, neurogenesis, and neuroprotection. Emerging evidence indicates that PCs also have a role in mediating cell-to-cell communication through the secretion of extracellular vesicles (EVs). Extracellular vesicles are cell-derived, micro- to nano-sized vesicles that transport cell constituents such as proteins, nucleic acids, and lipids from a parent originating cell to a recipient cell. PC-derived EVs (PC-EVs) play a crucial homeostatic role in neurovascular disease, as they promote angiogenesis, maintain the integrity of the blood-tissue barrier, and provide neuroprotection. The cargo carried by PC-EVs includes growth factors such as endothelial growth factor (VEGF), connecting tissue growth factors (CTGFs), fibroblast growth factors, angiopoietin 1, and neurotrophic growth factors such as brain-derived neurotrophic growth factor (BDNF), neuron growth factor (NGF), and glial-derived neurotrophic factor (GDNF), as well as cytokines such as interleukin (IL)-6, IL-8, IL-10, and MCP-1. The PC-EVs also carry miRNA and circular RNA linked to neurovascular health and the progression of several vascular and neuronal diseases. Therapeutic strategies employing PC-EVs have potential in the treatment of vascular and neurodegenerative diseases. This review discusses current research on the characteristic features of EVs secreted by PCs and their role in neuronal and vascular health and disease.
Publisher: American Physiological Society
Date: 12-2016
Abstract: Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild-type and TRAIL-deficient (Tnfsf10 −/− ) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10 −/− mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2018
DOI: 10.1038/S41598-018-36242-1
Abstract: Short chain fatty acids (SCFAs) are protective against inflammatory diseases. Free fatty acid receptor 2 (FFA2), is a target of SCFAs however, their selectivity for FFA2 over other FFA receptors is limited. This study aimed to functionally characterise 2-(4-chlorophenyl)-3-methyl-N-(thiazole-2-yl)butanamide (4CMTB) and 4-((4-(2-chlorophenyl)thiazole-2-yl)amino)-4oxo-3-phenylbutanoic acid (2CTAP), and their enantiomers, in modulating FFA2 activity. The racemic mixture ( R/S ) and its constituents ( R-) and ( S- ) 4CMTB or 2CTAP were used to stimulate human (h)FFA2 in the absence or presence of acetate. Calcium ions (Ca 2+ ), phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) and cyclic adenosine monophosphate (cAMP) were measured. R/S -4CMTB is a functionally selective ago-allosteric ligand that enhances Ca 2+ response to acetate. Both R/S -4CMTB and S -4CMTB are more potent activators of pERK1/2 and inhibitors of forskolin-induced cAMP than acetate. S -4CMTB increased neutrophil infiltration in intestinal ischemia reperfusion injury (IRI). 2CTAP inhibited constitutive Ca 2+ levels, antagonised acetate-induced pERK1/2 and prevented damage following IRI. This study characterises enantiomers of functionally selective ligands for FFA2 in cells stably expressing hFFA2. It highlights the novel roles of selective FFA2 enantiomers 4CMTB and 2CTAP on Ca 2+ , pERK1/2 and cAMP and their roles as allosteric modulators which, may assist in efforts to design novel therapeutic agents for FFA2-driven inflammatory diseases.
Publisher: Informa UK Limited
Date: 19-03-2020
Publisher: Wiley
Date: 13-12-2019
DOI: 10.1111/RESP.13453
Publisher: American Physiological Society
Date: 2019
DOI: 10.1152/AJPLUNG.00306.2018
Abstract: Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01–25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10–25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.
Publisher: Public Library of Science (PLoS)
Date: 09-2017
Publisher: American Thoracic Society
Date: 11-2010
Publisher: Elsevier BV
Date: 2022
Publisher: American Thoracic Society
Date: 08-2013
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1038/S41374-018-0146-0
Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive and devastating chronic lung condition that has a significant global burden, both medically and financially. Currently there are no medications that can alter the course of disease. At best, the drugs in clinical practice provide symptomatic relief to suffering patients by alleviating acute exacerbations. Most of current clinical research activities are in late severe disease with lesser attention given to early disease manifestations. There is as yet, a lack of understanding of the underlying mechanisms of disease progression and the molecular switches that are involved in their manifestation. Small airway fibrosis and obliteration are known to cause fixed airflow obstruction in COPD, and the consequential damage to the lung has an early onset. So far, there is little evidence of the mechanisms that underlie this aspect of pathology. However, emerging research confirms that airway epithelial reprogramming or epithelial to mesenchymal transition (EMT) is a key mechanism that drives fibrotic remodelling changes in smokers and patients with COPD. A recent study by Lai et al. further highlights the importance of EMT in smoking-related COPD pathology. The authors identify HB-EGF, an EGFR ligand, as a key driver of EMT and a potential new therapeutic target for the amelioration of EMT and airway remodelling. There are also wider implications in lung cancer prophylaxis, which is another major comorbidity associated with COPD. We consider that improved molecular understanding of the intricate pathways associated with epithelial cell plasticity in smokers and patients with COPD will have major therapeutic implications.
Publisher: European Respiratory Society (ERS)
Date: 13-11-2019
Publisher: Oxford University Press (OUP)
Date: 02-2016
DOI: 10.1095/BIOLREPROD.115.135848
Abstract: The theory of fetal origins of adult disease was first proposed in 1989, and in the decades since, a wide range of other diseases from obesity to asthma have been found to originate in early development. Because mammalian oocyte development begins in fetal life it has been suggested that environmental and lifestyle factors of the mother could directly impact the fertility of subsequent generations. Cigarette smoke is a known ovotoxicant in active smokers, yet disturbingly 13% of Australian and 12% of US women continue to smoke throughout pregnancy. The focus of our investigation was to characterize the adverse effects of smoking on ovary and oocyte quality in female offspring exposed in utero. Pregnant mice were nasally exposed to cigarette smoke for 12 wk throughout pregnancy/lactation, and ovary and oocyte quality of the F1 (maternal smoke exposed) generation was examined. Neonatal ovaries displayed abnormal somatic cell proliferation and increased apoptosis, leading to a reduction in follicle numbers. Further investigation found that altered somatic cell proliferation and reduced follicle number continued into adulthood however, apoptosis did not. This reduction in follicles resulted in decreased oocyte numbers, with these oocytes found to have elevated levels of oxidative stress, altered metaphase II spindle, and reduced sperm-egg interaction. These ovarian and oocyte changes ultimately lead to subfertility, with maternal smoke-exposed animals having smaller litters and also taking longer to conceive. In conclusion, our results demonstrate that in utero and lactational exposure to cigarette smoke can have long-lasting effects on the fertility of the next generation of females.
Publisher: Wiley
Date: 21-06-2017
DOI: 10.1111/ALL.13212
Abstract: Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase-2A (PP2A) is an abundant serine/threonine phosphatase with anti-inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL Acute AAD was induced in C57BL/6 mice by intraperitoneal sensitization with ovalbumin (OVA) in combination with intranasal (i.n) exposure to OVA. Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite (HDM) extract. Mice were treated with vehicle, FTY720, AAL AAL These findings highlight the potential of combination therapies that enhance PP2A and inhibit proteasome activity as novel therapeutic strategies for asthma.
Publisher: Wiley
Date: 23-08-2021
DOI: 10.1111/ALL.14548
Publisher: Public Library of Science (PLoS)
Date: 22-12-2015
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Wiley
Date: 06-1994
DOI: 10.1111/J.1432-1033.1994.TB18946.X
Abstract: In soluble and particulate extracts from muscle D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] are metabolised stepwise to inositol. Ins(1,4,5)P3 is rapidly dephosphorylated to D-myo-inositol 1,4-bisphosphate then to D-myo-inositol 4-phosphate and finally inositol. In soluble extracts Ins(1,3,4,5)P4 is dephosphorylated to D-myo-inositol 1,3,4-trisphosphate then sequentially to D-myo-inositol 3,4-bisphosphate, D-myo-inositol 3-phosphate and inositol, while in particulate extracts D-myo-inositol 1,3-bisphosphate is the predominant inositol bisphosphate formed. Dephosphorylation of these inositol polyphosphates is Mg2+ dependent and inhibited by D-2,3-bisphosphoglyceric acid. Ins(1,4,5)P3 is also phosphorylated to form Ins(1,3,4,5)P4 in soluble extracts by Ins(1,4,5)P3 3-kinase. Ins(1,4,5)P3 3-kinase activity is Mg2+ and ATP dependent and is stimulated by Ca2+ and calmodulin. Particulate (sarcotubular) inositol polyphosphate 5-phosphatase (5-phosphatase) is found in membranes which are intimately involved in excitation-contraction coupling and the generation of the primary Ca2+ signal of muscle cells. Particulate 5-phosphatase had the highest specific activity in the transverse-tubule membrane, when compared to the terminal cisternae and longitudinal-tubule membranes of the sarcoplasmic reticulum. Particulate Ins(1,3,4,5)P4-3-phosphatase activity was also detected after fractionation of solubilised sarcotubular membranes by DEAE-Sephacel. Particulate 5-phosphatase activity was purified 25,600-fold to a specific activity of 25.6 mumol Ins(1,4,5)P3 hydrolysed.min-1.mg protein-1, after DEAE-Sephacel and novel affinity chromatography using D-2,3-bisphosphoglycerate/agarose and Sepharose-4B-immobilised Ins(1,4,5)P3-analog matrices. Purified particulate 5-phosphatase had apparent Km of 46.3 microM and 1.9 microM and Vmax of 115 and 0.046 mumol substrate hydrolysed.min-1.mg protein-1, for Ins(1,4,5)P3 and Ins(1,3,4,5)P4, respectively. In contrast, purified soluble type I 5-phosphatase had apparent Km of 8.9 microM and 1.1 microM and Vmax of 3.55 and 0.13 mumol substrate hydrolysed.min-1.mg protein-1, for Ins(1,4,5P3 and Ins(1,3,4,5)P4, respectively. As in other cells, muscle 5-phosphatases have a lower affinity, but a higher capacity to metabolise Ins(1,4,5)P3 than Ins(1,3,4,5)P4. Soluble type I 5-phosphatase may have a functional role in the metabolism of both inositol polyphosphates, while particulate 5-phosphatase may primarily metabolise Ins(1,4,5)P3. Purified Ins(1,4,5)P3 3-kinase had an apparent Km of 0.42 microM and a Vmax of 4.12 nmol Ins(1,4,5)P3 phosphorylated.min-1.mg protein-1. The profile of inositol polyphosphate metabolism in muscle is similar to that reported in other tissues.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: American Thoracic Society
Date: 2017
Publisher: Frontiers Media SA
Date: 16-04-2019
Publisher: American Physiological Society
Date: 06-2020
DOI: 10.1152/AJPENDO.00513.2019
Abstract: Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum ( Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi P 0.001 and P 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi ( P 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF 2α ) by 53–83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE 2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice ( P 0.01 to P 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE 2 in mouse uterine horn and cervix.
Publisher: MDPI AG
Date: 14-04-2023
DOI: 10.3390/MOLECULES28083475
Abstract: Plant-derived compounds, specifically antioxidants, have played an important role in scavenging the free radicals present under diseased conditions. The persistent generation of free radicals in the body leads to inflammation and can result in even more severe diseases such as cancer. Notably, the antioxidant potential of various plant-derived compounds prevents and deregulates the formation of radicals by initiating their decomposition. There is a vast literature demonstrating antioxidant compounds’ anti-inflammatory, anti-diabetic, and anti-cancer potential. This review describes the molecular mechanism of various flavonoids, such as quercetin, kaempferol, naringenin, epicatechin, and epicatechin gallate, against different cancers. Additionally, the pharmaceutical application of these flavonoids against different cancers using nanotechnologies such as polymeric, lipid-based nanoparticles (solid–lipid and liquid–lipid), liposomes, and metallic nanocarriers is addressed. Finally, combination therapies in which these flavonoids are employed along with other anti-cancer agents are described, indicating the effective therapies for the management of various malignancies.
Publisher: American Society for Microbiology
Date: 15-09-2013
DOI: 10.1128/JVI.03437-12
Abstract: Influenza A H10N7 virus with a hemagglutinin gene of North American origin was detected in Australian chickens and poultry abattoir workers in New South Wales, Australia, in 2010 and in chickens in Queensland, Australia, on a mixed chicken and domestic duck farm in 2012. We investigated their genomic origins by sequencing full and partial genomes of H10 viruses isolated from wild aquatic birds and poultry in Australia and analyzed them with all available avian influenza virus sequences from Oceania and representative viruses from North America and Eurasia. Our analysis showed that the H10N7 viruses isolated from poultry were similar to those that have been circulating since 2009 in Australian aquatic birds and that their initial transmission into Australia occurred during 2007 and 2008. The H10 viruses that appear to have developed endemicity in Australian wild aquatic birds were derived from several viruses circulating in waterfowl along various flyways. Their hemagglutinin gene was derived from aquatic birds in the western states of the United States, whereas the neuraminidase was closely related to that from viruses previously detected in waterfowl in Japan. The remaining genes were derived from Eurasian avian influenza virus lineages. Our analysis of virological data spanning 40 years in Oceania indicates that the long-term evolutionary dynamics of avian influenza viruses in Australia may be determined by climatic changes. The introduction and long-term persistence of avian influenza virus lineages were observed during periods with increased rainfall, whereas bottlenecks and extinction were observed during phases of widespread decreases in rainfall. These results extend our understanding of factors affecting the dynamics of avian influenza and provide important considerations for surveillance and disease control strategies.
Publisher: American Society for Clinical Investigation
Date: 06-04-2017
Publisher: IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund
Date: 2017
Publisher: Elsevier BV
Date: 05-2014
Publisher: Elsevier BV
Date: 08-2019
Publisher: Routledge
Date: 20-05-2018
Publisher: Wiley
Date: 07-08-2023
DOI: 10.1002/MED.21908
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.CELLSIG.2016.01.009
Abstract: Chronic respiratory diseases are driven by inflammation, but some clinical conditions (severe asthma, COPD) are refractory to conventional anti-inflammatory therapies. Thus, novel anti-inflammatory strategies are necessary. The mRNA destabilizing protein, tristetraprolin (TTP), is an anti-inflammatory molecule that functions to induce mRNA decay of cytokines that drive pathogenesis of respiratory disorders. TTP is regulated by phosphorylation and protein phosphatase 2A (PP2A) is responsible for dephosphorylating (and hence activating) TTP, amongst other targets. PP2A is activated by small molecules, FTY720 and AAL(S), and in this study we examine whether these compounds repress cytokine production in a cellular model of airway inflammation using A549 lung epithelial cells stimulated with tumor necrosis factor α (TNFα) in vitro. PP2A activators significantly increase TNFα-induced PP2A activity and inhibit mRNA expression and protein secretion of interleukin 8 (IL-8) and IL-6 two key pro-inflammatory cytokines implicated in respiratory disease and TTP targets. The effect of PP2A activators is not via an increase in TNFα-induced TTP mRNA expression instead we demonstrate a link between PP2A activation and TTP anti-inflammatory function by showing that specific knockdown of TTP with siRNA reversed the repression of TNFα-induced IL-8 and IL-6 mRNA expression and protein secretion by FTY720. Therefore we propose that PP2A activators affect the dynamic equilibrium regulating TTP shifting the equilibrium from phosphorylated (inactive) towards unphosphorylated (active) but unstable TTP. PP2A activators boost the anti-inflammatory function of TTP and have implications for future pharmacotherapeutic strategies to combat inflammation in respiratory disease.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.CLIM.2013.12.003
Abstract: Recent genetic, structural and functional studies have identified the airway and lung epithelium as a key orchestrator of the immune response. Further, there is now strong evidence that epithelium dysfunction is involved in the development of inflammatory disorders of the lung. Here we review the characteristic immune responses that are orchestrated by the epithelium in response to erse triggers such as pollutants, cigarette smoke, bacterial peptides, and viruses. We focus in part on the role of epithelium-derived interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), as well as CC family chemokines as critical regulators of the immune response. We cite ex les of the function of the epithelium in host defense and the role of epithelium dysfunction in the development of inflammatory diseases.
Publisher: Oxford University Press (OUP)
Date: 17-08-2020
DOI: 10.1002/JLB.3MR0720-472RR
Abstract: The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, is one of the most well-characterized inflammasomes, activated by pathogen-associated molecular patterns and damage-associated molecular patterns, including from commensal or pathogenic bacterial and viral infections. The NLRP3 inflammasome promotes inflammatory cell recruitment and regulates immune responses in tissues such as the gastrointestinal tract and the lung, and is involved in many diseases that affect the gut and lung. Recently, the microbiome in the gut and the lung, and the crosstalk between these organs (gut–lung axis), has been identified as a potential mechanism that may influence disease in a bidirectional manner. In this review, we focus on themes presented in this area at the 2019 World Congress on Inflammation. We discuss recent evidence on how the microbiome can affect NLRP3 inflammasome responses in the gut and lung, the role of this inflammasome in regulating gut and lung inflammation in disease, and its potential role in the gut–lung axis. We highlight the exponential increase in our understanding of the NLRP3 inflammasome due to the synthesis of the NLRP3 inflammasome inhibitor, MCC950, and propose future studies that may further elucidate the roles of the NLRP3 inflammasome in gut and lung diseases.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-2013
Abstract: Type I interferons (IFNs) are critical cytokines involved in host defense against pathogens, particularly viruses. IFN-ɛ is an IFN-like gene encoded within the type I IFN locus in mice and humans whose function has not been characterized. Fung et al. (p. 1088 ) created mice with a genetic deletion in Ifn -ɛ and found that, like other type I IFNs, IFN-ɛ signals through the IFN-α receptors 1 and 2. However, unlike these other cytokines, which are primarily expressed by immune cells and are induced upon immune cell triggering, IFN-ɛ was expressed exclusively by epithelial cells of the female reproductive tract in both mice and humans and its expression was hormonally regulated. IFN-ɛ–deficient mice were more susceptible to infection with herpes simplex virus 2 and Chlamydia muridarum , two common sexually transmitted pathogens.
Publisher: Oxford University Press (OUP)
Date: 25-08-2015
Abstract: Inflammatory bowel disease is associated with a number of comorbidities that arise at extraintestinal sites, including the lung. Pulmonary manifestations reported in inflammatory bowel disease include bronchiectasis, chronic bronchitis and importantly, a range of subclinical respiratory abnormalities that are often overlooked in routine clinical evaluation. Whereas evidence for the pulmonary manifestations of Inflammatory bowel disease is increasing, little is known about the immunologic and physiologic mechanisms regulating cross-talk between the gut and lung during disease. This review examines reported lung involvement in Inflammatory bowel disease and discusses the possible immune pathways that underlie pulmonary pathologies. These mechanisms include dysfunctional immune-cell homing, systemic inflammation, and microbial dysbiosis all of which may contribute to Inflammatory bowel disease-induced pulmonary inflammation. These mechanisms are discussed in the context of our current knowledge of the shared mucosal immune system and the immunology of Inflammatory bowel disease.
Publisher: Informa UK Limited
Date: 06-2016
DOI: 10.1071/MU16006
Publisher: Wiley
Date: 17-08-2020
DOI: 10.1111/ALL.14535
Publisher: Elsevier BV
Date: 06-2014
Publisher: Universitas Islam Indonesia (Islamic University of Indonesia)
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 18-03-2020
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 06-12-2017
DOI: 10.1007/S13346-016-0349-0
Abstract: Biofilm comprises a community of microorganisms which form on medical devices and can lead to various threatening infections. It is a major concern in various respiratory diseases like cystic fibrosis, chronic obstructive pulmonary disease, etc. The treatment strategies for such infections are difficult due to the resistance of the microflora existing in the biofilms against various antimicrobial agents, thus posing threats to the patient population. The present era witnesses the beginning of research to understand the biofilm physiology and the associated microfloral ersity by applying -omics approaches. There is very limited information about how the deposition of biofilm on the respiratory devices and lung itself affects the drug delivered, the delivery system, and other implications. The present mini review summarizes the basic introduction to the biofilms and its avoidance using various drug delivery systems with special emphasis on the respiratory diseases. Understanding the approaches, principles, and modes of drug delivery involved in preventing biofilm deposition will be of interest to both biological and formulation scientists, thereby opening avenues to explore the new vistas in biofilm research for identifying better treatments for pulmonary infectious diseases.
Publisher: Wiley
Date: 23-03-2018
DOI: 10.1111/CEA.13109
Abstract: Adipose tissue-derived inflammation is linked to obesity-related comorbidities. This study aimed to quantify and immuno-phenotype adipose tissue macrophages (ATMs) from obese asthmatics and obese non-asthmatics and to examine associations between adipose tissue, systemic and airway inflammation. Visceral (VAT) adipose tissue and subcutaneous (SAT) adipose tissue were collected from obese adults undergoing bariatric surgery and processed to obtain the stromovascular fraction. Pro-inflammatory (M1) and anti-inflammatory (M2) macrophages were quantified by flow cytometry. Cytospins of induced sputum were stained for differential cell counts. Plasma C-reactive protein (CRP) and CD163 were measured by ELISA. VAT contained a higher number of ATMs compared to SAT. A higher percentage of M1 ATMs was observed in VAT of obese asthmatics compared to obese non-asthmatics. The M1:M2 ratio in VAT was negatively associated with FEV Visceral inflammation with increased pro-inflammatory macrophages (M1) occurs in obese asthma and may be a determinant of systemic inflammation and asthma severity.
Publisher: Springer Singapore
Date: 2019
Publisher: The American Association of Immunologists
Date: 15-02-2008
DOI: 10.4049/JIMMUNOL.180.4.2225
Abstract: There is strong epidemiological evidence that Chlamydia infection can lead to exacerbation of asthma. However, the mechanism(s) whereby chlamydial infection, which normally elicits a strong Th type 1 (Th1) immune response, can exacerbate asthma, a disease characterized by dominant Th type 2 (Th2) immune responses, remains unclear. In the present study, we show that Chlamydia muridarum infection of murine bone marrow-derived dendritic cells (BMDC) modulates the phenotype, cytokine secretion profile, and Ag-presenting capability of these BMDC. Chlamydia-infected BMDC express lower levels of CD80 and increased CD86 compared with noninfected BMDC. When infected with Chlamydia, BMDC secrete increased TNF-α, IL-6, IL-10, IL-12, and IL-13. OVA peptide-pulsed infected BMDC induced significant proliferation of transgenic CD4+ DO11.10 (D10) T cells, strongly inhibited IFN-γ secretion by D10 cells, and promoted a Th2 phenotype. Intratracheal transfer of infected, but not control noninfected, OVA peptide-pulsed BMDC to naive BALB/c mice, which had been i.v. infused with naive D10 T cells, resulted in increased levels of IL-10 and IL-13 in bronchoalveolar lavage fluid. Recipients of these infected BMDC showed significant increases in airways resistance and decreased airways compliance compared with mice that had received noninfected BMDC, indicative of the development of airways hyperreactivity. Collectively, these data suggest that Chlamydia infection of DCs allows the pathogen to deviate the induced immune response from a protective Th1 to a nonprotective Th2 response that could permit ongoing chronic infection. In the setting of allergic airways inflammation, this infection may then contribute to exacerbation of the asthmatic phenotype.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Bentham Science Publishers Ltd.
Date: 2021
DOI: 10.2174/1381612826666200728151610
Abstract: Curcumin is a major curcuminoid present in turmeric. The compound is attributed to various therapeutic properties, which include anti-oxidant, anti-inflammatory, anti-bacterial, anti-malarial, and neuroprotection. Due to its therapeutic potential, curcumin has been employed for centuries in treating different ailments. Curcumin has been investigated lately as a novel therapeutic agent in the treatment of cancer. However, the mechanisms by which curcumin exerts its cytotoxic effects on malignant cells are still not fully understood. One of the main limiting factors in the clinical use of curcumin is its poor bioavailability and rapid elimination. Advancements in drug delivery systems such as nanoparticle-based vesicular drug delivery platforms have improved several parameters, namely, drug bioavailability, solubility, stability, and controlled release properties. The use of curcumin-encapsulated niosomes to improve the physical and pharmacokinetic properties of curcumin is one such approach. This review provides an up-to-date summary of nanoparticle-based vesicular drug carriers and their therapeutic applications. Specifically, we focus on niosomes as novel drug delivery formulations and their potential in improving the delivery of challenging small molecules, including curcumin. Overall, the applications of such carriers will provide a new direction for novel pharmaceutical drug delivery, as well as for biotechnology, nutraceutical, and functional food industries.
Publisher: Public Library of Science (PLoS)
Date: 13-10-2010
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 09-03-2020
Publisher: Future Medicine Ltd
Date: 04-2022
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1038/S41385-019-0163-3
Abstract: Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1β levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1β in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.
Publisher: The American Association of Immunologists
Date: 05-2013
DOI: 10.4049/JIMMUNOL.190.SUPP.136.3
Abstract: Cigarette smoke-induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been h ered by the lack of an animal model that mimics the human disease in a short time-frame.We have created a mouse model of cigarette smoke-induced COPD that develops the hallmark features of the human condition in a short amount of time. Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathological features of COPD were assessed. The roles of macrophages and mast cell (MC) tryptase in pathogenesis were evaluated using depletion and in vitro studies and MC protease-6 deficient mice. After 8 weeks of smoke exposure, wild-type mice developed chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid-resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart, and increased susceptibility to respiratory infections also were observed. We demonstrate here that macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced pro-inflammatory responses from cultured macrophages. This model can be used to better understand multiple aspects of COPD pathogenesis.
Publisher: American Thoracic Society
Date: 05-2010
DOI: 10.1164/AJRCCM-CONFERENCE.2010.181.1_MEETINGABSTRACTS.A5588
Publisher: Wiley
Date: 26-09-2014
DOI: 10.1002/ART.38773
Abstract: The spondyloarthritides share genetic susceptibility, interleukin-23 (IL-23) dependence, and the involvement of microbiota. The aim of the current study was to elucidate how host genetics influence gut microbiota and the relationship between microbiota and organ inflammation in spondyloarthritides. BALB/c ZAP-70(W163C) -mutant (SKG) mice, Toll-like receptor 4 (TLR-4)-deficient SKG mice, and wild-type BALB/c mice were housed under specific pathogen-free conditions. SKG and wild-type BALB/c mice were maintained under germ-free conditions, and some of these mice were recolonized with altered Schaedler flora. All of the mice were injected intraperitoneally with microbial β-1,3-glucan (curdlan). Arthritis, spondylitis, and ileitis were assessed histologically. Microbiome composition was analyzed in serial fecal s les obtained from mice that were co-housed beginning at the time of weaning, using 454 pyrosequencing. Infiltrating cells and cytokines in the peritoneal cavity were measured by flow cytometry and enzyme-linked immunosorbent assay. Cytokine, endoplasmic reticulum (ER) stress marker, and tight junction protein transcription was measured by quantitative real-time polymerase chain reaction. Microbiota content and response to curdlan varied according to whether T cell receptor signal strength was normal or was impaired due to the ZAP-70(W163C) mutation. Curdlan triggered acute inflammation regardless of the presence of the SKG allele or microbiota. However, no or limited microbiota content attenuated the severity of arthritis. In contrast, ileal IL-23 expression, ER stress, lymph node IL-17A production, goblet cell loss, and ileitis development were microbiota-dependent. Ileitis but not arthritis was suppressed by microbiota transfer upon co-housing SKG mice with wild-type BALB/c mice, as well as by TLR-4 deficiency. The interaction between immunogenetic background and host microbiota leads to an IL-23-dependent loss of mucosal function, triggering ileitis in response to curdlan.
Publisher: Begell House
Date: 2009
DOI: 10.1615/CRITREVIMMUNOL.V29.I4.10
Abstract: Chlamydia trachomatis is an obligate intracellular bacterial pathogen that infects the genital and ocular mucosa of humans, causing infections that can lead to pelvic inflammatory disease, infertility, and blinding trachoma. C. pneumoniae is a respiratory pathogen that is the cause of 12-15% of community-acquired pneumonia. Both chlamydial species were believed to be restricted to the epithelia of the genital, ocular, and respiratory mucosa however, increasing evidence suggests that both these pathogens can be isolated from peripheral blood of both healthy in iduals and patients with inflammatory conditions such as coronary artery disease and asthma. Chlamydia can also be isolated from brain tissues of patients with degenerative neurological disorders such as Alzheimer's disease and multiple sclerosis, and also from certain lymphomas. An increasing number of in vitro studies suggest that some chlamydial species can infect immune cells, at least at low levels. These infections may alter immune cell function in a way that promotes chlamydial persistence in the host and contributes to the progression of several chronic inflammatory diseases. In this paper, we review the evidence for the growth of Chlamydia in immune cells, particularly monocytes/macrophages and dendritic cells, and describe how infection may affect the function of these cells.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
Publisher: MDPI AG
Date: 08-04-2023
DOI: 10.3390/PHARMACEUTICS15041192
Abstract: Cancer-related death is a significant health and economic burden worldwide, and some conventional chemotherapy is associated with limited effectiveness in completely curing various cancers, severe adverse effects, and destruction of healthy cells. To overcome the complications associated with conventional treatment, metronomic chemotherapy (MCT) is extensively suggested. In this review, we aim to highlight the importance of MCT over conventional chemotherapeutic approach with emphasis on nanoformulations-based MCT, their mechanism, challenges, recent advances, and future perspectives. Nanoformulations-based MCT revealed remarkable antitumor activity in both preclinical and clinical settings. For ex le, the metronomic scheduling of oxaliplatin-loaded nanoemulsion and polyethylene glycol-coated stealth nanoparticles incorporating paclitaxel were proven very effective in tumor-bearing mice and rats, respectively. Additionally, several clinical studies have demonstrated the benefit of MCT with acceptable tolerance. Moreover, metronomic might be a promising treatment strategy for improving cancer care in low- and middle-income nations. However, an appropriate alternative to a metronomic regimen for an in idual ailment, suitable combinational delivery and scheduling, and predictive biomarkers are certain parts that remain unanswered. Further clinical-based comparative research studies are mandatory to be performed before entailing this treatment modality in clinical practice as alternative maintenance therapy or in place of transferring to therapeutic management.
Publisher: American Society for Microbiology
Date: 28-04-2020
Abstract: Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza.
Publisher: Hindawi Limited
Date: 05-10-2021
DOI: 10.1111/JFBC.13954
Abstract: Metastasis represents the leading cause of death in lung cancer patients. C-X-C Motif Chemokine Ligand 8 (CXCL-8), Chemokine (C-C motif) ligand 20 (CCL-20) and heme oxygenase -1 (HO-1) play an important role in cancer cell proliferation and migration. Berberine is an isoquinoline alkaloid isolated from several herbs in the Papaveraceae family that exhibits anti-inflammatory, anticancer and antidiabetic properties. Therefore, the aim of present study is to investigate the inhibitory potential of berberine monoolein loaded liquid crystalline nanoparticles (berberine-LCNs) against cancer progression. Berberine-LCNs were prepared by mixing berberine, monoolein and poloxamer 407 (P407) using ultrasonication method. A549 cells were treated with or without 5 µM dose of berberine LCNs for 24 hr and total cellular protein was extracted and further analyzed for the protein expression of CCl-20, CXCL-8 and HO-1 using human oncology array kit. Our results showed that berberine-LCNs significantly reduced the expression of CCl-20, CXCL-8 and HO-1 at dose of 5µM. Collectively, our findings suggest that berberine-LCNs have inhibitory effect on inflammation/oxidative stress related cytokines i.e. CCL20, CXCL-8, and HO-1 which could be a novel therapeutic target for the management of lung cancer. PRACTICAL APPLICATIONS: Berberine is an isoquinoline alkaloid extracted from various plants of Papaveraceae family. CXCL-8, CCL-20 and HO-1 play an important role in cancer progression. Our study showed that Berberine LCNs significantly downregulate the expression of CXCL-8, CCL-20 and HO-1 which suggests that Berberine loaded nanoparticles could be a promising therapeutic alternative for the management of lung cancer.
Publisher: MDPI AG
Date: 16-08-2022
DOI: 10.3390/MOLECULES27165219
Abstract: Stinging nettle (Urtica dioica L., Urticaceae) is commonly found in Asia, Africa, and Europe and has a long history of being used as food and traditional medicine. Recently, this plant is gaining attention as a highly nutritious food, where fresh leaves are dried and used as powder or in other forms. Leaves are rich in many bioactive compounds. This review aims to cover the traditional uses in food and medicine, as well as its nutritional composition, including its bioactive chemical constituents and reported food functional activities. Various bioactive chemical constituents have been isolated from stinging nettle to date, such as flavonoids, phenolic acids, amino acid, carotenoids, and fatty acids. Stinging nettle extracts and its compounds, such as rutin, kaempferol, and vitamin A, are also used for their nutritional properties and as anti-inflammatory and antioxidant agents. Future studies should focus on the proper formulation and stability testing of the functional foods containing stinging nettle and their detailed activities in clinical studies.
Publisher: The American Association of Immunologists
Date: 05-2012
DOI: 10.4049/JIMMUNOL.188.SUPP.175.18
Abstract: We have previously shown that chlamydial lung infections in early-life drive the development of chronic airway hyper-responsiveness (AHR). To elucidate the mechanisms involved, we used a murine model of chlamydial lung infection, to investigate the influence of IL-13 on infection and infection-induced AHR. Infected IL-13-/- mice had less severe infection, reduced inflammation (neutrophils, dendritic cells, macrophages and T cells), less mucus secreting cells (MSCs) in the airways and attenuated AHR. More severe infection in wild-type (WT) mice was associated with the development of alternatively activated macrophages (increased Arg-1, FIZZ-1 and Ym-1), which were suppressed in IL-13-/- mice. Surprisingly, infection of WT mice did not induce any detectable increase in IL-13 expression. However, infection decreased the level of the IL-13 decoy receptor (IL-13Rα2), which may allow constitutive IL-13 to signal. Interestingly, reconstitution of IL-13 in IL-13-/- mice restored infection-induced inflammation and MSC formation, but not AHR. Furthermore, infection-induced inflammation and mucus were Stat-6-independent, whilst infection-induced AHR was dependent upon Stat-6. Thus, early-life respiratory chlamydial infection results in decreased decoy receptor expression, which allows constitutive IL-13 to signal and promote more severe infection, which drives the development of chronic AHR that persists into adulthood.
Publisher: American Thoracic Society
Date: 05-2010
DOI: 10.1164/AJRCCM-CONFERENCE.2010.181.1_MEETINGABSTRACTS.A5599
Publisher: Wiley
Date: 11-2017
DOI: 10.1111/RESP.13206_3
Publisher: Informa UK Limited
Date: 31-05-2020
Publisher: European Respiratory Society (ERS)
Date: 17-03-2020
DOI: 10.1183/13993003.01340-2019
Abstract: Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma. We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild–moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV 1 ). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV 1 /forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules alent metal transporter 1 ( DMT1 ) and transferrin receptor 1 ( TFR1 ) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1 + macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo , including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses. Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
Publisher: Elsevier
Date: 2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-09-2021
DOI: 10.1126/SCIIMMUNOL.ABD0205
Abstract: SARS-CoV-2 evades immune recognition in humans but not bats, pointing to potential strategies for therapeutic intervention.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2023
Publisher: The American Association of Immunologists
Date: 05-2012
Abstract: Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2016
DOI: 10.1038/SREP37297
Abstract: Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E 2 (PGE 2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE 2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.
Publisher: Future Medicine Ltd
Date: 12-2020
Abstract: Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers IL-6, IL-8, IL-1β and TNF-α in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.JACI.2009.10.018
Abstract: Asthma typically originates in early-life, and the impact of infection during immunologic maturation is a critical factor in disease pathogenesis. The progression of aberrant T(H)2 cell responses and disease development has been attributed to a lack of infections. However, exposure to specific pathogens such as Chlamydia may alter immunologic programming and predispose to asthma. To investigate the effects of chlamydial infection at different ages on allergic airways disease in later life. Neonatal, infant, or adult BALB/c mice were infected and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Hallmark features of allergic airways disease were compared with uninfected allergic and nonallergic controls. Early-life (neonatal and infant) but not adult chlamydial infection enhanced the development of hallmark features of asthma in ovalbumin-induced allergic airways disease. Notably early-life infection increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness. Neonatal infection attenuated eosinophil influx and ovalbumin-specific T(H)2 cytokine release and numbers of activated myeloid dendritic cells (DCs) in lymph nodes. By contrast, infant infection augmented features of allergic inflammation with increased airway eosinophils, T(H)2 cytokine, and DC responses. Both neonatal and infant infection increased systemic DC-induced IL-13 release from CD4(+) T cells. The timing of infection had significant effects on lung structure because neonatal but not infant or adult infection induced increases in alveolar diameter. Early-life respiratory chlamydial infections modulate immune responses, alter lung function and structure, and enhance the severity of allergic airways disease in later life.
Publisher: American Chemical Society (ACS)
Date: 20-12-2020
Publisher: Elsevier BV
Date: 10-2019
Publisher: MDPI AG
Date: 24-05-2022
DOI: 10.3390/PHARMACEUTICS14061119
Abstract: Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer, which is a leading cause of cancer-related deaths worldwide. Berberine is an isoquinoline alkaloid that is commercially available for use as a supplement for the treatment of diabetes and cardiovascular diseases. However, the therapeutic benefits of berberine are limited by its extremely low bioavailability and toxicity at higher doses. Increasing evidence suggests that the incorporation of drug compounds in liquid crystal nanoparticles provides a new platform for the safe, effective, stable, and controlled delivery of the drug molecules. This study aimed to formulate an optimized formulation of berberine–phytantriol-loaded liquid crystalline nanoparticles (BP-LCNs) and to investigate the in vitro anti-cancer activity in a human lung adenocarcinoma A549 cell line. The BP-LCN formulation possessing optimal characteristics that was used in this study had a favorable particle size and entrapment efficiency rate (75.31%) and a superior drug release profile. The potential mechanism of action of the formulation was determined by measuring the mRNA levels of the tumor-associated genes PTEN, P53, and KRT18 and the protein expression levels with a human oncology protein array. BP-LCNs decreased the proliferation, migration, and colony-forming activity of A549 cells in a dose-dependent manner by upregulating the mRNA expression of PTEN and P53 and downregulating the mRNA expression of KRT18. Similarly, BP-LCNs also decreased the expression of proteins related to cancer cell proliferation and migration. This study highlights the utility of phytantriol-based LCNs in incorporating drug molecules with low GI absorption and bioavailability to increase their pharmacological effectiveness and potency in NSCLC.
Publisher: The American Association of Immunologists
Date: 05-2013
DOI: 10.4049/JIMMUNOL.190.SUPP.56.19
Abstract: RATIONALE MicroRNAs (miRNAs) are small non-coding RNA that can bind to multiple target mRNA to repress protein production. While the expressions of specific miRNAs are known to be dysregulated in multiple human diseases, the role of miRNAs in regulating bacterial infection is unclear. Our aim is to investigate the roles of miRNA in regulating these processes. METHODS BALB/c mice were challenged with low doses of NTHi. Lung miRNAs that were differentially expressed were identified by microarray. miRNA inhibitors (antagomirs) were used to knockdown miRNA expression to investigate the roles of miRNA in bacterial clearance in vitro and in vivo. RESULTS Upon NTHi infection, 20 miRNAs were up-regulated while 52 were down-regulated by & 2.5 fold. Interestingly, knockdown of a specific miRNA in vitro decreased bacterial load and increased phagocytosis by macrophages and neutrophils. Similarly, transfer of macrophages or neutrophils deficient in miRNA into naïve recipient mice leads to enhance clearance of the bacteria in vivo. This enhance clearance is independent of cellular infiltration. Inhibiting miRNA may play a protective role by enhancing the function of innate immune cells during bacterial infection. CONCLUSION Our study suggests that miRNA may play important roles in regulating the innate immune response to bacterial infection.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2020
DOI: 10.1186/S12885-020-6686-X
Abstract: Colorectal cancer (CRC) is the most common cancer and a leading cause of death worldwide. Extracellular matrix (ECM) proteins regulate tumor growth and development in CRC. Elastin (ELN) is a component of ECM proteins involved in the tumor microenvironment. However, the role of ELN in CRC remains unclear. In this study, we analyzed ELN gene expression in tumors from CRC patients and adjacent non-tumor colon tissues and healthy controls from two existing microarray datasets. ELN protein was measured in human normal colon cells and colon cancer epithelial cells and tumor development was assessed in colon epithelial cells cultured in medium with or without ELN peptide on plates coated with ELN recombinant protein. Control plates were coated with PBS only. We found ELN gene expression was increased in tumors from CRC patients compared to adjacent non-tumor tissues and healthy controls. ELN protein was increased in cancer cells compared to normal colon epithelial cells. Transforming growth factor beta (TGF-β) was a key cytokine to induce production of ECM proteins, but it did not induce ELN expression in colon cancer cells. Matrix metalloproteinase 9 ( MMP9 ) gene expression was increased, but that of MMP12 (elastase) did not change between CRC patients and control. Tissue inhibitor of metalloproteinases 3 ( TIMP3 ) gene expression was decreased in colon tissues from CRC patients compared to healthy controls. However, MMP9, MMP12 and TIMP3 proteins were increased in colon cancer cells. ELN recombinant protein increased proliferation and wound healing in colon cancer epithelial cells. This had further increased in cancer cells incubated in plates coated with recombinant ELN coated plate and in culture media containing ELN peptide. A potential mechanism was that ELN induced epithelial mesenchymal transition with increased alpha-smooth muscle actin and vimentin proteins but decreased E-cadherin protein. Tumor necrosis factor alpha ( TNF ) mRNA was also increased in CRC patients compared to controls. ELN recombinant protein induced further increases in TNF protein in mouse bone marrow derived macrophages after lipopolysaccharide stimulation. These data suggest ELN regulates tumor development and the microenvironment in CRC.
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Elsevier BV
Date: 03-2008
Publisher: Elsevier BV
Date: 08-2010
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.VACCINE.2007.09.034
Abstract: Asthma is a common inflammatory disease of the airways. Current therapies alleviate symptoms but do not treat the disease. We aim to develop effective immunomodulatory therapies (IMTs) for asthma that target the underlying causes of disease based on Streptococcus pneumoniae (Spn). The effect of Spn IMT on the development of asthma [allergic airways disease (AAD)] was determined in mice. Killed Spn was administered before, during or after ovalbumin sensitization, and the subsequent development of AAD was assessed. IMT attenuated T cell cytokine production, goblet cell hyperplasia, airways hyperresponsiveness (AHR), and eosinophil numbers in the blood, bronchoalveolar lavage fluid and peribronchial tissue. This indicates the potential of Spn as an IMT for asthma.
Publisher: American Society for Clinical Investigation
Date: 08-02-2018
Publisher: The American Association of Immunologists
Date: 15-11-2014
Abstract: The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7–driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R−/− cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 h ers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
Publisher: Bentham Science Publishers Ltd.
Date: 23-10-2020
DOI: 10.2174/1381612826666200610111013
Abstract: Many plant-based bioactive compounds have been serving as the origin of drugs since long ago and many of them have been proven to have medicinal value against various chronic diseases, including, cancer, arthritis, hepatic diseases, type-2 diabetes and cardiovascular diseases. However, their clinical applications have been limited due to their poor water solubility, stability, low bioavailability and extensive transformation due to the first-pass metabolism. The applications of nanocarriers have been proven to be able to improve the delivery of bioactive phytoconstituents, resulting in the enhancement of various pharmacokinetic properties and thereby increasing the therapeutic value of phytoconstituents. These biocompatible nanocarriers also exert low toxicity to healthy cells. This review focuses on the uses and applications of different types of nanocarriers to enhance the delivery of phytoconstituents for the treatment of various chronic diseases, along with comparisons related to bioavailability and therapeutic efficacy of nano phytoconstituents with native phytoconstituents.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2017
DOI: 10.1038/S41598-017-13888-X
Abstract: We explore potential dysregulation of macrophage phenotypes in COPD pathogenesis through integrated study of human small airway tissue, bronchoalveolar lavage (BAL) and an experimental murine model of COPD. We evaluated human airway tissue and BAL from healthy controls, normal lung function smokers (NLFS), and COPD subjects. Both small airways and BAL cells were immunohistochemically stained with anti-CD68 for total macrophages and with anti-CD163 for M2, and anti-iNOS for M1 macrophages. Multiplex ELISA measured BAL cytokines. Comparable cigarette smoke-induced experimental COPD mouse model was assessed for relevant mRNA profiles. We found an increase in pro-inflammatory M1s in the small airways of NLFS and COPD compared to controls with a reciprocal decrease in M2 macrophages, which remained unchanged among pathological groups. However, luminal macrophages showed a dominant M2 phenotype in both NLFS and COPD subjects. BAL cytokine skewed towards an M2 profile with increase in CCL22, IL-4, IL-13, and IL-10 in both NLFS and COPDs. The mouse-model of COPD showed similar increase in mRNA for M2 markers. Our finding suggests abnormal macrophage switching in both mucosal and luminal areas of COPD patients, that strongly associated with cytokine balance. There may be potential for beneficial therapeutic cytokine manipulation of macrophage phenotypes in COPD.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2020
Publisher: Wiley
Date: 15-05-2014
DOI: 10.1111/RESP.12316
Abstract: Airway epithelial cells represent the first line of defence against inhaled insults, including air pollution. Air pollution can activate innate immune signalling in airway epithelial cells leading to the production of soluble mediators that can influence downstream inflammatory cells. Our objective was to develop and validate a model of dendritic cell exposure to airway epithelial cell-conditioned media. After establishing the model, we explored how soluble mediators released from airway epithelial cells in response to air pollution influenced the phenotype of dendritic cells. Human airway epithelial cells were cultured under control and urban particulate matter (PM10) exposure conditions with or without pharmacological inhibitors of the uric acid pathway. Culture supernatants were collected for conditioned media experiments with peripheral blood mononuclear cell-derived dendritic cells analysed by flow cytometry. Monocytes derived from peripheral blood mononuclear cells cultured in interleukin-4 and granulocyte macrophage colony stimulating factor differentiated into immature dendritic cells that phenotypically differentiated into mature dendritic cells in response to conditioned media from phorbol myristate acetate-activated THP-1 monocytes. Exposure of immature dendritic cells to conditioned media from airway epithelial cells exposed to PM10 resulted in dendritic cell maturation that was independent of uric acid. We present a conditioned media model useful for interrogating the contribution of soluble mediators produced by airway epithelial cells to dendritic cell phenotype and function. Furthermore, we demonstrate that PM10 exposure induces airway epithelial cell production of soluble mediators that induce maturation of dendritic cells independent of uric acid.
Publisher: Wiley
Date: 27-07-2021
DOI: 10.1111/IBI.12866
Publisher: Oxford University Press (OUP)
Date: 10-2019
DOI: 10.1093/EURHEARTJ/EHZ746.0894
Abstract: Cardiac fibrosis is a severe consequence of cardiovascular disease and aging, in which we currently have no effective treatments. The mechanisms underpinning the development of cardiac fibrosis remains poorly understood. Our preliminary data suggested extracellular matrix protein 1 (ECM1) is involved in cardiac fibrosis. We therefore aimed to investigate the role of ECM1 in several fibrotic cardiac diseases. Young and ageing (3m/18m) male C57BL/6 mice, and primary mouse cardiac fibroblast (cFB) cultures, commercial human cardiac fibroblasts (Hu-cFB), human coronary artery endothelial cell (HCAEC)/smooth muscle cell (HCASMC), and human cardiac myocyte (HCM) cell lines were used. Young mice were subject to myocardial infarction (MI, 3-day/28-day, n=6/6), or pressure overload (TAC, 3-day/13-week, n=4/4). Left ventricle (LV) was collected at all time-points, and at 18m (ageing n=3). Spleen and bone marrow was extracted from young control mice. Hu-cFB cells were treated with recombinant ECM1 (20ng/ml) for either 10, 30 or 50 min, or 48h. Immunoblotting was conducted on all s les, qPCR on LV tissue only, density gradient centrifugation and multicolour flow cytometry coupled with fluorescent ECM1 mRNA in-situ hybridisation (FISH-Flow) on bone marrow cells. ECM1 expression was upregulated in ageing LV (mRNA 2.2±0.1-fold, p=0.0002 protein 2.0-fold, p=0.0006), day-3 post-MI (mRNA, 4.9±2.0-fold, p=0.004 protein, 3.0-fold, p=0.004), a trend of ECM1 upregulation was observed at day-28 post-MI (mRNA, 13.2±12.0-fold, p=0.003 protein, 1.8-fold, p=0.2), but no change post-TAC. Both ERK1/2 and AKT phosphorylation was upregulated 10 min post-ECM1 treatment of Hu-cFBs (ERK1/2, 2.0-fold, p .0001 AKT, 1.9-fold, p .0001), and Collagen-I protein expression was upregulated 48h post-ECM1 treatment (1.9-fold, p=0.004). ECM1 protein was not expressed in cFB, Hu-cFB, HCAEC, HCASMC or HCM, however ECM1 protein was highly expressed in spleen and bone marrow to a greater extent in granulocytes compared to monocytes (p=0.004). tSNE analysis of ECM1 mRNA FISH-Flow revealed ECM1+ are highly granular, moderate to large in size, and express (to varying levels) CD45, CD11b, CD11c, F4/80, Ly6-C, Ly-6G, and FcεrI-α. However ECM1+ cells did not express markers indicative of smaller cells (CD3 or MHC II). These data demonstrate that ECM1 plays a role in ageing and post-MI fibrosis. Although ECM1 was not produced by resident cardiac cells, it was highly expressed in spleen and bone marrow specifically, large, granular bone marrow cell sub-types such as granulocytes and/or macrophages. Our data suggest ECM1 is expressed by cardiac infiltrating leukocytes to provoke fibroblast collagen expression in a disease specific manner potentially via the ERK1/2 and/or AKT pathway activation. Therefore, ECM1 warrants further investigation, and may be a promising target for the treatment of fibrotic cardiac diseases. John hunter hospital charitable trust, Hunter medical research institute (HMRI) grants
Publisher: Elsevier BV
Date: 10-2017
Publisher: Begell House
Date: 2018
Publisher: Wiley
Date: 25-03-2019
DOI: 10.5694/MJA2.50117
Abstract: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball s ling) and by Facebook advertising. Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders) early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball s ling did not increase recruitment. Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.
Publisher: Springer Science and Business Media LLC
Date: 22-05-2019
Publisher: European Respiratory Society
Date: 15-09-2018
Publisher: Springer International Publishing
Date: 2020
Publisher: Wiley
Date: 17-01-2014
DOI: 10.1002/AR.22867
Abstract: Preterm infants who receive supplemental oxygen for prolonged periods are at increased risk of impaired lung function later in life. This suggests that neonatal hyperoxia induces persistent changes in small conducting airways (bronchioles). Although the effects of neonatal hyperoxia on alveolarization are well documented, little is known about its effects on developing bronchioles. We hypothesized that neonatal hyperoxia would remodel the bronchiolar walls, contributing to altered lung function in adulthood. We studied three groups of mice (C57BL/6J) to postnatal day 56 (P56 adulthood) when they either underwent lung function testing or necropsy for histological analysis of the bronchiolar wall. One group inhaled 65% O2 from birth until P7, after which they breathed room air this group experienced growth restriction (HE+GR group). We also used a group in which hyperoxia-induced GR was prevented by dam rotation (HE group). A control group inhaled room air from birth. At P56, the bronchiolar epithelium of HE mice contained fewer Clara cells and more ciliated cells, and the bronchiolar wall contained ∼25% less collagen than controls in HE+GR mice the bronchiolar walls had ∼13% more collagen than controls. Male HE and HE+GR mice had significantly thicker bronchiolar epithelium than control males and altered lung function (HE males: greater dynamic compliance HE+GR males: lower dynamic compliance). We conclude that neonatal hyperoxia remodels the bronchiolar wall and, in adult males, affects lung function, but effects are altered by concomitant growth restriction. Our findings may partly explain the reports of poor lung function in ex-preterm children and adults.
Publisher: Wiley
Date: 22-11-2023
DOI: 10.1111/RESP.14401
Abstract: Smoking disturbs the bronchial-mucus-barrier. This study assesses the cellular composition and gene expression shifts of the bronchial-mucus-barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single-cell-RNA-sequencing (scRNA-seq) based cellular deconvolution (CD) can predict cell-type composition in RNA-seq data. RNA-seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers 18 ex-smokers), 77 participants without COPD (40 never-smokers 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non-COPD-smokers). Differential gene expression was used to investigate gene expression shifts. The CD-derived goblet cell ratios were validated by correlating with staining-derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (false discovery rate p-value < 0.05). Both CD methods indicate a shift in bronchial-mucus-barrier cell composition towards goblet cells in COPD and non-COPD-smokers compared to ex- and never-smokers. It shows that the effect was reversible within a year of smoking cessation. A reduction of ciliated and basal cells was observed with current smoking, which resolved following smoking cessation. The expression of mucin and sodium channel (ENaC) genes, but not chloride channel genes, were altered in COPD and current smokers compared to never smokers or ex-smokers. The goblet cell-derived staining scores correlate with CD-derived goblet cell ratios. Smoking alters bronchial-mucus-barrier cell composition, transcriptome and increases mucus production. This effect is partly reversible within a year of smoking cessation. CD methodology can predict goblet-cell percentages from RNA-seq.
Publisher: Informa UK Limited
Date: 18-11-2009
DOI: 10.3109/10715760903362576
Abstract: Potential bacterial pathogens are found in the airways in several diseases that are associated with neutrophilic inflammation. The aim of this study was to characterize subjects with stable asthma, with no symptoms of respiratory infection, to assess whether key potentially pathogenic bacteria were present in significant quantities in the airways and to correlate this with the pattern of airway inflammation and oxidative stress. Subjects with stable asthma (n = 115) and healthy controls (n = 8) underwent clinical assessment, including hypertonic saline challenge combined with sputum induction. A significant load of potentially pathogenic bacteria (> 10(6) cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils, sputum IL-8 and 8-isoprostane concentrations. The role of bacteria in potentiating neutrophilic asthma warrants further investigation. Therapies such as antibiotic and antioxidant treatment may be most effective in this sub-group of patients.
Publisher: European Respiratory Society (ERS)
Date: 30-09-2019
DOI: 10.1183/16000617.0096-2019
Abstract: Severe steroid-resistant asthma is clinically important, as patients with this form of the disease do not respond to mainstay corticosteroid therapies. The heterogeneity of this form of asthma and poor understanding of the pathological mechanisms involved hinder the identification of therapeutic targets and the development of more effective therapies. A major limiting factor in the understanding of severe steroid-resistant asthma is the existence of multiple endotypes represented by different immunological and inflammatory phenotypes, particularly in adults. Several clinical and experimental studies have revealed associations between specific respiratory infections and steroid-resistant asthma in adults. Here, we discuss recent findings from other authors as well as our own studies that have developed novel experimental models for interrogating the association between respiratory infections and severe steroid-resistant asthma. These models have enabled the identification of new therapies using macrolides, as well as several novel disease mechanisms, including the microRNA-21 hosphoinositide 3-kinase/histone deacetylase 2 axis and NLRP3 inflammasomes, and highlight the potential of these mechanisms as therapeutic targets.
Publisher: Future Science Ltd
Date: 04-2018
Abstract: Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.
Publisher: Springer Singapore
Date: 2019
Publisher: Informa UK Limited
Date: 10-2017
DOI: 10.2147/COPD.S151142
Publisher: Elsevier BV
Date: 02-1994
DOI: 10.1016/0898-6568(94)90081-7
Abstract: A myoplasmic 3-kinase was detected in porcine skeletal muscle that phosphorylated [3H]Ins(1,4,5)P3 [D-myo-inositol(1,4,5)trisphosphate] to [3H]Ins(1,3,4,5)P4 [D-myo-inositol(1,3,4,5)tetrakisphosphate]. The Ins(1,4,5)P3 3-kinase activity was ATP- and Mg(2+)-dependent, and was activated by Ca2+ and calmodulin. Ins(1,4,5)P3 3-kinase activity was purified 2632-fold from soluble extracts of skeletal muscle by a combination of DEAE-Sephacel, heparin-Agarose and Ins(1,4,5)P3 structural-analogue affinity chromatography. The highest specific activity obtained was 10.6 nmol of Ins(1,4,5)P3 phosphorylated/min/mg protein. The partially purified enzyme had a mean Km and Vmax of 0.46 microM and 3.15 nmol/min/mg protein for Ins(1,4,5)P3 metabolism, respectively. After analytical gel filtration two forms of soluble Ins(1,4,5)P3 3-kinase were observed with M(r) of 39,000 and 62,000. As in other cell types, muscle Ins(1,4,5)P3 3-kinase was soluble, and had a higher affinity but a lower capacity to metabolize Ins(1,4,5)P3 in comparison to Ins(1,4,5)P3 5-phosphatase.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.CBI.2020.108947
Abstract: Inflammatory responses play a remarkable role in the mechanisms of acute and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and lung cancer. Currently, there is a resurgence in the use of drugs from natural sources for various ailments as potent therapeutics. Berberine, an alkaloid prominent in the Chinese traditional system of medicine has been reported to exert therapeutic properties in various diseases. Nevertheless, the number of studies focusing on the curative potential of berberine in inflammatory diseases involving the respiratory system is limited. In this review, we have attempted to discuss the reported anti-inflammatory properties of berberine that function through several pathways such as, the NF-κB, ERK1/2 and p38 MAPK pathways which affect several pro-inflammatory cytokines in the pathophysiological processes involved in chronic respiratory diseases. This review would serve to provide valuable information to researchers who work in this field and a new direction in the field of drug discovery with respect to respiratory diseases.
Publisher: American Thoracic Society
Date: 05-2020
DOI: 10.1164/AJRCCM-CONFERENCE.2020.201.1_MEETINGABSTRACTS.A4473
Publisher: Elsevier BV
Date: 10-2009
Publisher: European Respiratory Society
Date: 09-2015
Publisher: Informa UK Limited
Date: 2015
DOI: 10.3402/IEE.V5.28383
Abstract: The zoonotic bacterium C ylobacter jejuni has a broad host range but is especially associated with birds, both domestic and wild. Earlier studies have indicated thrushes of the genus Turdus in Europe to be frequently colonized with C. jejuni, and predominately with host-associated specific genotypes. The European Blackbird Turdus merula has a large distribution in Europe, including some oceanic islands, and was also introduced to Australia by European immigrants in the 1850s. The host specificity and temporal stability of European Blackbird C. jejuni was investigated with multilocus sequence typing in a set of isolates collected from Sweden, Australia, and The Azores. Remarkably, we found that the Swedish, Australian, and Azorean isolates were genetically highly similar, despite extensive spatial and temporal isolation. This indicates adaptation, exquisite specificity, and stability in time for European Blackbirds, which is in sharp contrast with the high levels of recombination and mutation found in poultry-related C. jejuni genotypes. The maintenance of host-specific signals in spatially and temporally separated C. jejuni populations suggests the existence of strong purifying selection for this bacterium in European Blackbirds.
Publisher: Wiley
Date: 12-2018
Publisher: The American Association of Immunologists
Date: 04-2009
DOI: 10.4049/JIMMUNOL.182.SUPP.130.7
Abstract: Bronchial epithelial cells are the natural human host for influenza infection but knowledge about the innate immune response is limited. Study objectives characterise the innate immune response of bronchial epithelial cells to infection with human influenza A virus and relate this to virus replication. Methods Influenza H3N2, A/Wellington/2004 (H3N2) was cultured and titred using plaque assays on Manine Darby Kidney Cells. Primary bronchial epithelial cells (PBECs) were obtained by bronchoscopy and cultured. Their response was compared to an epithelial cell line, Calu 3. Innate immune response was measured by the induction of mRNA by real time PCR for RIG-I, MDA-5, TLR-3, PKR, interferon (IFN)-β. Protein expression was then measured by western blot in cell lysate or supernatant. Results H3N2 replicated to significantly higher titres in Calu 3 cells 2.8x106 PFU/ml compared to PBECs 789 PFU/ml (p& .001). Following infection there was greater than 20 fold induction of RIG-I mRNA in both cells, strong protein expression in PBECs by 24hr, only faint expression in Calu3. A thousand fold induction in MDA-5 mRNA was seen in PBECs at 48hr less than 20 fold in Calu3. Induction of IFN-β mRNA by 24hr and protein release in the supernatant was seen in both cells by 6hr. Conclusions H3N2 replicates less well in PBECs and this is associated with more vigorous induction of RIG-I during early infection and later induction of MDA-5 mRNA.
Publisher: European Respiratory Society (ERS)
Date: 05-2017
Publisher: American Thoracic Society
Date: 04-2016
Publisher: Wiley
Date: 16-01-2019
DOI: 10.1002/PATH.5211
Abstract: Lung development is a complex process mediated through the interaction of multiple cell types, factors and mediators. In mice, it starts as early as embryonic day 9 and continues into early adulthood. The process can be separated into five different developmental stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar. Whilst lung bud formation and branching morphogenesis have been studied extensively, the mechanisms of alveolarisation are incompletely understood. Aberrant lung development can lead to deleterious consequences for respiratory health such as bronchopulmonary dysplasia (BPD), a disease primarily affecting preterm neonates, which is characterised by increased pulmonary inflammation and disturbed alveolarisation. While the deleterious effects of type 1-mediated inflammatory responses on lung development have been well established, the role of type 2 responses in postnatal lung development remains poorly understood. Recent studies indicate that type 2-associated immune cells, such as group 2 innate lymphoid cells and alveolar macrophages, are increased in number during postnatal alveolarisation. Here, we present the current state of understanding of the postnatal stages of lung development and the key cell types and mediators known to be involved. We also provide an overview of how stem cells are involved in lung development and regeneration, and the negative influences of respiratory infections. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 03-2020
Publisher: Bentham Science Publishers Ltd.
Date: 24-01-2018
DOI: 10.2174/2211738505666170808095258
Abstract: The respiratory tract as a non-invasive route of drug administration is gaining increasing attention in the present time on achieving both local and the systemic therapeutic effects. Success in achieving pulmonary delivery, requires overcoming barriers including mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time and rate to target sites. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically. We searched and reviewed the literature focusing on chitosan and chitosan derivative based nanocarrier systems used in pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for this purpose. Chitosan, a natural linear bio-polyaminosaccharide is central in the development of novel drug delivery systems (NDDS) including nanoparticles for use in the treatment of various respiratory diseases. It achieves this through its unique properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation across membranes. It also achieves sustained and targeted effects, primary requirements for an effective pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, employed in the management of respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis. This review will be of interest to both the biological and formulation scientists as it provides a summary on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available for pulmonary drug delivery and so this area has enormous potential in the field of respiratory science.
Publisher: Wiley
Date: 11-11-2021
DOI: 10.1111/CEA.13766
Abstract: Asthma is an airway inflammatory disease and a major health problem worldwide. Anti-inflammatory steroids and bronchodilators are the gold-standard therapy for asthma. However, they do not prevent the development of the disease, and critically, a subset of asthmatics are resistant to steroid therapy. To elucidate the therapeutic potential of human β-defensins (hBD), such as hBD2 mild to moderate and severe asthma. We investigated the role of hBD2 in a steroid-sensitive, house dust mite-induced allergic airways disease (AAD) model and a steroid-insensitive model combining ovalbumin-induced AAD with C muridarum (Cmu) respiratory infection. In both models, we demonstrated that therapeutic intranasal application of hBD2 significantly reduced the influx of inflammatory cells into the bronchoalveolar lavage fluid. Furthermore, key type 2 asthma-related cytokines IL-9 and IL-13, as well as additional immunomodulating cytokines, were significantly decreased after administration of hBD2 in the steroid-sensitive model. The suppression of inflammation was associated with improvements in airway physiology and treatment also suppressed airway hyper-responsiveness (AHR) in terms of airway resistance and compliance to methacholine challenge. These data indicate that hBD2 reduces the hallmark features and has potential as a new therapeutic agent in allergic and especially steroid-resistant asthma.
Publisher: Future Science Ltd
Date: 09-2022
Publisher: American Chemical Society (ACS)
Date: 03-10-2019
DOI: 10.1021/ACS.JMEDCHEM.9B01283
Abstract: Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-links in extracellular matrix proteins, namely, collagen and elastin, and is indicated in fibrotic diseases. Herein, we report the identification and subsequent optimization of a series of indole-based fluoroallylamine inhibitors of LOXL2. The result of this medicinal chemistry c aign is
Publisher: Elsevier BV
Date: 05-2008
Publisher: Elsevier BV
Date: 10-2020
Publisher: Bentham Science Publishers Ltd.
Date: 27-09-2018
DOI: 10.2174/1389450119666180326122831
Abstract: In the United States, the estimated number of new cancer cases in 2018 will be approx. 1.7 million. Historically, combination chemotherapy has been the primary choice of treatment. However, chemotherapeutics have pharmaceutical limitations, among which include problems with stability and aqueous solubility. Likewise, dose limiting toxicity is significant with nonspecific toxicity to healthy cells, hair loss, loss of appetite, peripheral neuropathy and diarrhea being typical side effects. The emergence of Multidrug resistance (MDR) also presents s a significant challenge for the successful treatment of cancer whereby cancer cells become cross resistant to many of the chemotherapeutic agents used. Nanotechnology presents a new frontier for cancer treatment. It holds potential in minimizing systemic toxicity through the development of functionalized particles for targeted treatment. They also provide an alternative strategy to circumvent multidrug resistance as they have a capacity to by-pass the drug efflux mechanism associated with this phenotype. Aside from the advantages they offer in treatment, nanoparticles are also emerging to be valuable diagnostic entities. This article highlights the various ways nanotechnology is being used to improve the treatment and management of cancer. We also discuss the opportunities and obstacles in this area and provide an up to date review of progress in the treatment of cancer.
Publisher: American Physiological Society
Date: 12-10-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-08-2020
DOI: 10.1126/SCITRANSLMED.AAW9009
Abstract: FFA4 receptor agonism corrects dysfunctional lung responses and inflammation in models and is a potential target for inflammatory lung disease.
Publisher: Springer International Publishing
Date: 2023
Publisher: MDPI AG
Date: 18-06-2020
DOI: 10.3390/MICROORGANISMS8060921
Abstract: Viral respiratory infections (VRIs) can spread quickly and cause enormous morbidity and mortality worldwide. These events pose serious threats to public health due to time lags in developing vaccines to activate the acquired immune system. The high variability of people’s symptomatic responses to viral infections, as illustrated in the current COVID-19 pandemic, indicates the potential to moderate the severity of morbidity from VRIs. Growing evidence supports roles for probiotic bacteria (PB) and prebiotic dietary fiber (DF) and other plant nutritional bioactives in modulating immune functions. While human studies help to understand the epidemiology and immunopathology of VRIs, the chaotic nature of viral transmissions makes it difficult to undertake mechanistic study where the pre-conditioning of the metabolic and immune system could be beneficial. However, recent experimental studies have significantly enhanced our understanding of how PB and DF, along with plant bioactives, can significantly modulate innate and acquired immunity responses to VRIs. Synbiotic combinations of PB and DF potentiate increased benefits primarily through augmenting the production of short-chain fatty acids (SCFAs) such as butyrate. These and specific plant polyphenolics help to regulate immune responses to both restrain VRIs and temper the neutrophil response that can lead to acute respiratory distress syndrome (ARDS). This review highlights the current understanding of the potential impact of targeted nutritional strategies in setting a balanced immune tone for viral clearance and reinforcing homeostasis. This knowledge may guide the development of public health tactics and the application of functional foods with PB and DF components as a nutritional approach to support countering VRI morbidity.
Publisher: MDPI AG
Date: 09-02-2023
DOI: 10.3390/IJMS24043500
Abstract: Lung cancer is the leading cause of cancer-related deaths globally, in part due to a lack of early diagnostic tools and effective pharmacological interventions. Extracellular vesicles (EVs) are lipid-based membrane-bound particles released from all living cells in both physiological and pathological states. To understand the effects of lung-cancer-derived EVs on healthy cells, we isolated and characterized EVs derived from A549 lung adenocarcinoma cells and transferred them to healthy human bronchial epithelial cells (16HBe14o). We found that A549-derived EVs carry oncogenic proteins involved in the pathway of epithelial to mesenchymal transition (EMT) that are regulated by β-catenin. The exposure of 16HBe14o cells to A549-derived EVs resulted in a significant increase in cell proliferation, migration, and invasion via upregulating EMT markers such as E-Cadherin, Snail, and Vimentin and cell adhesion molecules such as CEACAM-5, ICAM-1, and VCAM-1, with concomitant downregulation of EpCAM. Our study suggests a role for cancer-cell-derived EVs to induce tumorigenesis in adjacent healthy cells by promoting EMT via β-catenin signaling.
Publisher: MDPI AG
Date: 02-2021
Abstract: Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches.
Publisher: Informa UK Limited
Date: 02-01-2020
Publisher: Frontiers Media SA
Date: 05-11-2015
Publisher: The American Association of Immunologists
Date: 05-2015
DOI: 10.4049/JIMMUNOL.194.SUPP.64.6
Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and causes significant healthcare and economic burden. Cigarette smoking is a major risk factor. There is a lack of effective treatments for COPD due to the poor understanding of the underlining mechanisms. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is implicated in respiratory diseases such as asthma and pulmonary fibrosis. However, the role of TRAIL in the pathogenesis of COPD is unknown. In this study, TRAIL mRNA expression and/or protein levels in the lung (airway and parenchyma) and serum were increased in a mouse model of cigarette smoke-induced experimental COPD. Genetic deletion of TRAIL significantly reduced cigarette smoke-induced pulmonary inflammation, expression of key pro-inflammatory mediators, emphysema-like alveolar enlargement and improved lung function in experimental COPD. Interestingly, genetic deletion of TRAIL led to spontaneous small airway remodelling characterized by increased airway epithelial cell thickness and collagen deposition. Importantly, antibody-mediated neutralization of TRAIL reduced cigarette smoke-induced pulmonary inflammation, emphysema-like alveolar enlargement and small airway remodelling. Our study is the first to show that TRAIL plays an important role in the pathogenesis of COPD and provides further evidence for TRAIL being a pivotal inflammatory cytokine in respiratory diseases.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Wiley
Date: 06-04-2011
Publisher: European Respiratory Society
Date: 05-03-2020
Publisher: Wiley
Date: 30-10-2020
DOI: 10.1111/RESP.13722
Abstract: COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non-antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia-inducible factor (HIF)-1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF-1α expression can upregulate the platelet-activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR-dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF-1α in augmenting PAFR-dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia-induced inflammation, HIF-1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.COPH.2013.03.005
Abstract: Airway inflammation underpins the pathogenesis of the major human chronic respiratory diseases. It is now well recognized that respiratory infections with bacteria and viruses are important in the induction, progression and exacerbation of these diseases. There are no effective therapies that prevent or reverse these events. The development and use of mouse models are proving valuable in understanding the role of infection in disease pathogenesis. They have recently been used to show that infections in early life alter immune responses and lung structure to increase asthma severity, and alter immune responses in later life to induce steroid resistance. Infection following smoke exposure or in experimental chronic obstructive pulmonary disease exacerbates inflammation and remodeling, and worsens cystic fibrosis. Further exploration of these models will facilitate the identification of new therapeutic approaches and the testing of new preventions and treatments.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.BIOCEL.2015.08.014
Abstract: The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin 300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.
Publisher: Oxford University Press (OUP)
Date: 10-04-2017
Abstract: What effect does multigenerational (F2) and transgenerational (F3) cigarette smoke exposure have on female fertility in mice? Cigarette smoking has a multigenerational effect on female fertility. It has been well established that cigarette smoking decreases female fertility. Furthermore, a growing body of evidence suggests that smoking during pregnancy decreases the fertility of daughters and increases cancer and asthma incidence in grandchildren and great-grandchildren. Six-week-old C57BL/6 female mice were exposed nasally to cigarette smoke or room air (controls) for 5 weeks prior to being housed with males. Females continued to be exposed to smoke throughout pregnancy and lactation until pups were weaned. A subset of F1 female pups born to these smoke and non-smoke exposed females were bred to create the F2 grandmaternal exposed generation (multigenerational). Finally, a subset of F2 females were bred to create the F3 great-grandmaternal exposed generation (transgenerational). The reproductive health of F2 and F3 females was examined at 8 weeks and 9 months. Ovarian and oocyte quality was examined in smoke exposed and control animals. A small-scale fertility trial was performed before ovarian changes were examined using ovarian histology and immunofluorescence and/or immunoblotting analysis of markers of apoptosis (TUNEL) and proliferation (proliferating cell nuclear antigen (PCNA) and anti-Mullerian hormone (AMH)). Oocyte quality was examined using immunocytochemistry to analyze the metaphase II spindle and ploidy status. Parthenogenetic activation of oocytes was used to investigate meiosis II timing and preimplantation embryo development. Finally, diestrus hormone serum levels (FSH and LH) were quantified. F2 smoke exposed females had no detectable change in ovarian follicle quality at 8 weeks, although by 9 months ovarian somatic cell proliferation was reduced (P = 0.0197) compared with non-smoke exposed control. Further investigation revealed changes between control and smoke exposed F2 oocyte quality, including altered meiosis II timing at 8 weeks (P = 0.0337) and decreased spindle pole to pole length at 9 months (P = 0.0109). However, no change in preimplantation embryo development was observed following parthenogenetic activation. The most noticeable effect of cigarette smoke exposure was related to the subfertility of F2 females F2 smoke exposed females displayed significantly increased time to conception (P = 0.0042) and significantly increased lag time between pregnancies (P = 0.0274) compared with non-smoke exposed F2 females. Conversely, F3 smoke exposed females displayed negligible oocyte and follicle changes up to 9 months of age, and normal preimplantation embryo development. None. This study focused solely on a mouse model of cigarette smoke exposure to simulate human exposure. Our results demonstrate that grandmaternal cigarette smoke exposure reduces female fertility in mice, highlighting the clinical need to promote cessation of cigarette smoking in pregnant women. This study was funded by the Australian Research Council, National Health and Medical Research Council, Hunter Medical Research Institute, Newcastle Permanent Building Society Charitable Trust, and the University of Newcastle Priory Research Centers in Chemical Biology, Healthy Lungs and Grow Up Well. The authors declare no conflict of interest.
Publisher: American Thoracic Society
Date: 05-2012
DOI: 10.1164/AJRCCM-CONFERENCE.2012.185.1_MEETINGABSTRACTS.A5702
Publisher: BMJ
Date: 22-10-2015
Publisher: Elsevier BV
Date: 2018
DOI: 10.1038/MI.2017.56
Publisher: Public Library of Science (PLoS)
Date: 06-10-2011
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 12-2010
Publisher: Springer Science and Business Media LLC
Date: 28-11-2017
DOI: 10.1007/S13346-017-0440-1
Abstract: MicroRNAs (miRNAs) represent a new class of diagnostic and prognostic biomarker as well as new therapeutic targets in cancer therapy. miRNAs are gaining significant interest due to extensive advancements in knowledge since their discovery and, more recently, their translational application as therapeutic moieties and targets in the management of disease. miRNAs used in the treatment of cancer would position them as a new class of emerging therapeutic agents. Indeed, numerous candidate miRNAs have been identified as having therapeutic application in the treatment of cancer, but there is still much to learn about how to transform these into effective, patient-compliant, and targeted drug delivery systems. In this mini review, we discuss the utility and potential of nanotechnology in miRNA formulation and delivery with particular emphasis on cancer, including their role in conferring multidrug resistance and metastatic capacity. This review benefits both the formulation and biological scientists in understanding and exploring the new vistas of miRNA delivery using nanotechnology in the cancer clinically.
Publisher: Informa Healthcare
Date: 23-04-2014
DOI: 10.1517/17460441.2014.909805
Abstract: Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality and chronic morbidity. Inhalation of cigarette smoke is the principal risk factor for development of this disease. COPD is a progressive disease that is typically characterised by chronic pulmonary inflammation, mucus hypersecretion, airway remodelling and emphysema that collectively reduce lung function. There are currently no therapies that effectively halt or reverse disease progression. It is hoped that the development of animal models that develop the hallmark features of COPD, in a short time frame, will aid in the identifying and testing of new therapeutic approaches. The authors review the recent developments in mouse models of chronic cigarette smoke-induced COPD as well as the principal findings. Furthermore, the authors discuss the use of mouse models to understand the pathogenesis and the contribution of infectious exacerbations. They also discuss the investigations of the systemic co-morbidities of COPD (pulmonary hypertension, cachexia and osteoporosis). Recent advances in the field mark a point where animal models recapitulate the pathologies of COPD patients in a short time frame. They also reveal novel insights into the pathogenesis and potential treatment of this debilitating disease.
Publisher: Elsevier BV
Date: 03-2017
Publisher: Bentham Science Publishers Ltd.
Date: 02-12-2020
DOI: 10.2174/1871530320666200503053846
Abstract: The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its erse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
Publisher: MDPI AG
Date: 05-12-2022
DOI: 10.3390/NANO12234312
Abstract: Inflammation and oxidative stress are interrelated processes that represent the underlying causes of several chronic inflammatory diseases that include asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), allergies, diabetes, and cardiovascular diseases. Macrophages are key initiators of inflammatory processes in the body. When triggered by a stimulus such as bacterial lipopolysaccharides (LPS), these cells secrete inflammatory cytokines namely TNF-α that orchestrate the cellular inflammatory process. Simultaneously, pro-inflammatory stimuli induce the upregulation of inducible nitric oxide synthase (iNOS) which catalyzes the generation of high levels of nitric oxide (NO). This, together with high concentrations of reactive oxygen species (ROS) produced by macrophages, mediate oxidative stress which, in turn, exacerbates inflammation in a feedback loop, resulting in the pathogenesis of several chronic inflammatory diseases. Berberine is a phytochemical embedded with potent in vitro anti-inflammatory and antioxidant properties, whose therapeutic application is hindered by poor solubility and bioavailability. For this reason, large doses of berberine need to be administered to achieve the desired pharmacological effect, which may result in toxicity. Encapsulation of such a drug in liquid crystalline nanoparticles (LCNs) represents a viable strategy to overcome these limitations. We encapsulated berberine in phytantriol-based LCNs (BP-LCNs) and tested the antioxidant and anti-inflammatory activities of BP-LCNs in vitro on LPS-induced mouse RAW264.7 macrophages. BP-LCNs showed potent anti-inflammatory and antioxidant activities, with significant reduction in the gene expressions of TNF-α and iNOS, followed by concomitant reduction of ROS and NO production at a concentration of 2.5 µM, which is lower than the concentration of free berberine concentration required to achieve similar effects as reported elsewhere. Furthermore, we provide evidence for the suitability for BP-LCNs both as an antioxidant and as an anti-inflammatory agent with potential application in the therapy of chronic inflammatory diseases.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2018
DOI: 10.1038/S41598-018-30313-Z
Abstract: Genome-wide mRNA profiling in lung tissue from human and animal models can provide novel insights into the pathogenesis of chronic obstructive pulmonary disease (COPD). While 6 months of smoke exposure are widely used, shorter durations were also reported. The overlap of short term and long-term smoke exposure in mice is currently not well understood, and their representation of the human condition is uncertain. Lung tissue gene expression profiles of six murine smoking experiments (n = 48) were obtained from the Gene Expression Omnibus (GEO) and analyzed to identify the murine smoking signature. The “human smoking” gene signature containing 386 genes was previously published in the lung eQTL study (n = 1,111). A signature of mild COPD containing 7 genes was also identified in the same study. The lung tissue gene signature of “severe COPD” (n = 70) contained 4,071 genes and was previously published. We detected 3,723 differentially expressed genes in the 6 month-exposure mice datasets (FDR .1). Of those, 184 genes (representing 48% of human smoking) and 1,003 (representing 27% of human COPD) were shared with the human smoking-related genes and the COPD severity-related genes, respectively. There was 4-fold over-representation of human and murine smoking-related genes (P = 6.7 × 10 −26 ) and a 1.4 fold in the severe COPD -related genes (P = 2.3 × 10 −12 ). There was no significant enrichment of the mice and human smoking-related genes in mild COPD signature. These data suggest that murine smoke models are strongly representative of molecular processes of human smoking but less of COPD.
Publisher: Public Library of Science (PLoS)
Date: 20-04-2015
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
Publisher: Springer Science and Business Media LLC
Date: 03-11-2018
Publisher: Wiley
Date: 18-10-2020
DOI: 10.1111/CEA.13505
Abstract: Acute exacerbations of asthma represent a major burden of disease and are often caused by respiratory infections. Viral infections are recognized as significant triggers of exacerbations however, less is understood about the how microbial bioproducts such as the endotoxin (lipopolysaccharide (LPS)) trigger episodes. Indeed, increased levels of LPS have been linked to asthma onset, severity and steroid resistance. The goal of this study was to identify mechanisms underlying bacterial-induced exacerbations by employing LPS as a surrogate for infection. We developed a mouse model of LPS-induced exacerbation on the background of pre-existing type-2 allergic airway disease (AAD). LPS-induced exacerbation was characterized by steroid-resistant airway hyperresponsiveness (AHR) and an exaggerated inflammatory response distinguished by increased numbers of infiltrating neutrophils/macrophages and elevated production of lung inflammatory cytokines, including TNFα, IFNγ, IL-27 and MCP-1. Expression of the type-2 associated inflammatory factors such as IL-5 and IL-13 were elevated in AAD but not altered by LPS exposure. Furthermore, AHR and airway inflammation were no longer suppressed by corticosteroid (dexamethasone) treatment after LPS exposure. Depletion of pulmonary macrophages by administration of 2-chloroadenosine into the lungs suppressed AHR and reduced IL-13, TNFα and IFNγ expression. Blocking IL-13 function, through either IL-13-deficiency or administration of specific blocking antibodies, also suppressed AHR and airway inflammation. We present evidence that IL-13 and innate immune pathways (in particular pulmonary macrophages) contribute to LPS-induced exacerbation of pre-existing AAD and provide insight into the complex molecular processes potentially underlying microbial-induced exacerbations.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2018
Publisher: Frontiers Media SA
Date: 05-04-2018
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.CBI.2019.02.021
Abstract: Macrophages are considered as the most flexible cells of the hematopoietic system that are distributed in the tissues to act against pathogens and foreign particles. Macrophages are essential in maintaining homeostatic tissue processes, repair and immunity. Also, play important role in cytokine secretion and signal transduction of the infection so as to develop acquired immunity. Accounting to their involvement in pathogenesis, macrophages present a therapeutic target for the treatment of inflammatory respiratory diseases. This review focuses on novel drug delivery systems (NDDS) including nanoparticles, liposomes, dendrimers, microspheres etc that can target alveolar macrophage associated with inflammation, intracellular infection and lung cancer. The physiochemical properties and functional moieties of the NDDS attributes to enhanced macrophage targeting and uptake. The NDDS are promising for sustained drug delivery, reduced therapeutic dose, improved patient compliance and reduce drug toxicity. Further, the review also discuss about modified NDDS for specificity to the target and molecular targeting via anti-microbial peptides, kinases, NRF-2 and phosphodiesterase.
Publisher: American Thoracic Society
Date: 05-2012
DOI: 10.1164/AJRCCM-CONFERENCE.2012.185.1_MEETINGABSTRACTS.A4980
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1038/MI.2015.104
Abstract: Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.
Publisher: The American Association of Immunologists
Date: 05-2015
DOI: 10.4049/JIMMUNOL.194.SUPP.65.8
Abstract: Chlamydia trachomatis is the most common bacterial STI and frequently results in reproductive tract (RT) sequelae such as pelvic inflammatory disease and infertility. However, the immune processes involved in the clearance and immunopathology of Chlamydia infection are not well understood. In previous studies we showed that IFN-ε, a novel type I IFN that is exclusively and constitutively expressed in the female RT, plays an important role in protecting against Chlamydia infections. Here, we examined the effects of IFN-ɛ on cellular responses in the female RT in order to elucidate the mechanisms by which IFN-ɛ protects against Chlamydia infections. Female WT and IFN-ε-/- C57BL/6 mice were pre-treated with progesterone and infected intra-vaginally with Chlamydia muridarum or sham-infected. Uterine horns were harvested and the effects of IFN-ε deficiency on Chlamydia infection, immune factor expression and cellular infiltration were assessed using real-time qPCR and flow cytometry. We show that IFN-ε-/- mice have increased Chlamydia 16S expression in the upper RT which correlated with fewer NK cells and tissue-resident uterine NK cells at 3 days post infection. IFN-γ+ CD45+ cells were also decreased in the infected IFN-ε-/- mice, of which over 60% were NK cells. These changes were associated with reduced iNOS and STAT1 expression. These findings suggest that IFN-ε may protect against Chlamydia RT infections by potentiating the recruitment of protective IFN-γ-producing NK cells.
Publisher: American Thoracic Society
Date: 05-2019
Publisher: Portland Press Ltd.
Date: 07-2019
DOI: 10.1042/CS20181009
Abstract: Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, chronic obstructive pulmonary disease (COPD) accounting for approximately 3 million deaths annually. Frequent acute exacerbations (AEs) of COPD (AECOPD) drive clinical and functional decline in COPD and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs. Infections with a small subgroup of pathogens precipitate the majority of AEs and consequently constitute a significant comorbidity in COPD. However, current pharmacological interventions are ineffective in preventing infectious exacerbations and their treatment is compromised by the rapid development of antibiotic resistance. Thus, alternative preventative therapies need to be considered. Pathogen adherence to the pulmonary epithelium through host receptors is the prerequisite step for invasion and subsequent infection of surrounding structures. Thus, disruption of bacterial–host cell interactions with receptor antagonists or modulation of the ensuing inflammatory profile present attractive avenues for therapeutic development. This review explores key mediators of pathogen–host interactions that may offer new therapeutic targets with the potential to prevent viral/bacterial-mediated AECOPD. There are several conceptual and methodological hurdles h ering the development of new therapies that require further research and resolution.
Publisher: Wiley
Date: 05-03-2019
DOI: 10.1002/PATH.5242
Abstract: Acute kidney injury (AKI) remains a global challenge and, despite the availability of dialysis and transplantation, can be fatal. Those that survive an AKI are at increased risk of developing chronic kidney disease and end stage renal failure. Understanding the fundamental mechanisms underpinning the pathophysiology of AKI is critical for developing novel strategies for diagnosis and treatment. A growing body of evidence indicates that lifying type 2 immunity may have therapeutic potential in kidney injury and disease. Of particular interest are the recently described subset of innate immune cells, termed group 2 innate lymphoid cells (ILCs). Group 2 ILCs are crucial tissue-resident immune cells that maintain homeostasis and regulate tissue repair at multiple organ sites, including the kidney. They are critical mediators of type 2 immune responses following infection and injury. The existing literature suggests that activation of group 2 ILCs and production of a local type 2 immune milieu is protective against renal injury and associated pathology. In this review, we describe the emerging role for group 2 ILCs in renal homeostasis and repair. We provide an in-depth discussion of the most recent literature that use preclinical models of AKI and assess the therapeutic effect of modulating group 2 ILC function. We debate the potential for targeting these cells as novel cellular therapies in AKI and discuss the implications for future studies and translation. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: American Thoracic Society
Date: 15-09-2007
Publisher: Wiley
Date: 11-2017
Publisher: Wiley
Date: 11-2017
Publisher: Springer Science and Business Media LLC
Date: 11-02-1998
Abstract: Kluyveromyces lactis is a petite-negative yeast that does not form viable mitochondrial genome-deletion mutants (petites) when treated with DNA-targeting drugs. Loss of mtDNA is lethal for this yeast but mutations at three loci termed MGI, for mitochondrial genome integrity, can suppress this lethality. The three loci encode the alpha-, beta- and gamma-subunits of mitochondrial F1-ATPase. In this study we report the isolation and characterization of the KlATPdelta gene encoding the delta-subunit of F1-ATPase. The deduced protein contains 158 amino acids showing 72% identity to the protein from Saccharomyces cerevisiae and a putative mitochondrial targeting sequence of 23 amino acids. Disruption of the gene causes cells to become respiratory deficient while the introduction of ATPdelta from S. cerevisiae restores growth on glycerol. Cells with a disrupted ATPdelta gene, like strains with disruptions of alpha-, beta- and gamma-F1-subunits, do not produce petite mutants when treated with ethidium bromide. However, unlike strains with disruptions in the three largest F1-subunits, disruption of ATPdelta in the presence of some mgi alleles does not abolish the Mgi- phenotype. By contrast, elimination of ATPdelta in other mgi strains removes resistance to ethidium bromide and rho0 mutants are not formed. Hence the ATPdelta subunit of F1-ATPase, while not mandatory for a Mgi- phenotype, aids some mgi alleles in suppressing rho0 lethality.
Publisher: Wiley
Date: 15-07-2016
DOI: 10.1038/CTI.2016.37
Publisher: American Thoracic Society
Date: 2015
Publisher: Bentham Science Publishers Ltd.
Date: 31-12-2020
DOI: 10.2174/1871527319999200817112427
Abstract: Tobacco smoke is not only a leading cause for chronic obstructive pulmonary disease, cardiovascular disorders, and lung and oral cancers, but also causes neurological disorders such as Alzheimer ’s disease. Tobacco smoke consists of more than 4500 toxic chemicals, which form free radicals and can cross blood-brain barrier resulting in oxidative stress, an extracellular amyloid plaque from the aggregation of amyloid β (Aβ) peptide deposition in the brain. Further, respiratory infections such as Chlamydia pneumoniae, respiratory syncytial virus have also been involved in the induction and development of the disease. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. The review article sheds light on the role of smoking and respiratory infections in causing oxidative stress and neuroinflammation, resulting in Alzheimer& #039 s disease (AD). This review will be of interest to scientists and researchers from biological and medical science disciplines, including microbiology, pharmaceutical sciences and the translational researchers, etc. The increasing understanding of the relationship between chronic lung disease and neurological disease is two-fold. First, this would help to identify the risk factors and possible therapeutic interventions to reduce the development and progression of both diseases. Second, this would help to reduce the probable risk of development of AD in the population prone to chronic lung diseases.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JCRC.2014.07.013
Abstract: Neutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondrial DNA (mtDNA) under certain conditions, which is potently proinflammatory. We hypothesized that injury and orthopedic trauma surgery would induce NET production with mtDNA as a structural component. Neutrophils were isolated 8 trauma patients requiring orthopedic surgery postinjury and up to 5 days postoperatively. Four healthy volunteers provided positive and negative controls. Total hip replacement patients acted as an uninjured surgical control group. Neutrophil extracellular traps were visualized with DNA (Hoechst 33342TM/Sytox Green/MitoSox/MitoTracker) stains using live cell fluorescence microscopy with downstream quantitative polymerase chain reaction analysis of DNA composition. Neutrophil extracellular traps were present after injury in all 8 trauma patients. They persisted for 5 days postoperatively. Delayed surgery resulted in NET resolution, but they reformed postoperatively. Total hip replacement patients developed NETs postoperatively, which resolved by day 5. Quantitative polymerase chain reaction analysis of NET-DNA composition revealed that NETs formed after injury and surgery were made of mtDNA with no detectable nuclear DNA component. Neutrophil extracellular traps formed after major trauma and subsequent surgery contain mtDNA and represent a novel marker of heightened innate immune activation. They could be considered when timing surgery after trauma to prevent systemic NET-induced inflammatory complications.
Publisher: American Thoracic Society
Date: 04-2009
DOI: 10.1164/AJRCCM-CONFERENCE.2009.179.1_MEETINGABSTRACTS.A4251
Publisher: Public Library of Science (PLoS)
Date: 20-03-2015
Publisher: Informa Healthcare
Date: 24-04-2009
DOI: 10.1517/14712590902916999
Abstract: Asthma is a common global health problem. Environmental exposures such as bacteria may protect against asthma development. This review aims to examine the possible protective role of pneumococcal infection and vaccination in asthma. A review of known experimental biology and human epidemiology relating to asthma and pneumococcal infection was performed. Pneumococcal infection can modulate components of allergic airways disease such as airways hyperresponsiveness and airway eosinophilia. Exposure to killed pneumococcus can reproduce these effects and the mechanism may involve control by T regulatory cells. Pneumococcal immunoregulatory therapy is a potentially important approach to asthma management that requires further evaluation in well-designed research studies.
Publisher: Wiley
Date: 25-03-2019
DOI: 10.1002/JCP.28482
Abstract: Chronic obstructive pulmonary disease accounts as the leading cause of mortality worldwide prominently affected by genetic and environmental factors. The disease is characterized by persistent coughing, breathlessness airways inflammation followed by a decrease in forced expiratory volume 1 and exacerbations, which affect the quality of life. Determination of genetic, epigenetic, and oxidant biomarkers to evaluate the progression of disease has proved complicated and challenging. Approaches including exome sequencing, genome‐wide association studies, linkage studies, and inheritance and segregation studies played a crucial role in the identification of genes, their pathways and variation in genes. This review highlights multiple approaches for biomarker and gene identification, which can be used for differential diagnosis along with the genome editing tools to study genes associated with the development of disease and models their function. Further, we have discussed the approaches to rectify the abnormal gene functioning of respiratory tissues and various novel gene editing techniques like Zinc finger nucleases (ZFN), transcription activator‐like effector nucleases (TALEN), and clustered regulatory interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9).
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1038/MI.2015.111
Abstract: Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
Publisher: American Thoracic Society
Date: 05-2012
DOI: 10.1164/AJRCCM-CONFERENCE.2012.185.1_MEETINGABSTRACTS.A4988
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.ATHEROSCLEROSIS.2022.02.011
Abstract: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. A subgroup of participants at one centre (Canberra n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2006
DOI: 10.1007/S00705-006-0784-1
Abstract: Shorebirds on their southerly migration from Siberia to Australia, may pass through Asian regions currently experiencing outbreaks of highly pathogenic H5N1 influenza. To test for the presence of avian influenza viruses in migratory shorebirds arriving in Australia during spring 2004, 173 cloacal swabs were collected from six species. Ten swabs were positive for influenza A, with H4N8 viruses detected in five red-necked stints and H11N9 viruses detected in five sharp-tailed sandpipers. No H5N1 viruses were detected. All isolated viruses were non-pathogenic in domestic chickens. These results further demonstrate the potential for migratory shorebirds to carry and potentially spread influenza viruses.
Publisher: American Physiological Society
Date: 09-2023
DOI: 10.1152/AJPLUNG.00232.2022
Abstract: Influenza A virus (IAV) infection during pregnancy with asthma is a major health concern leading to increased morbidity for both mother and baby. Using murine models, we show that IAV infection in pregnancy with allergic airway disease is associated with impaired global antiviral and antimicrobial responses, increased lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Targeting specific β-defensins or microRNAs (miRNAs) may prove useful in future treatments for IAV infection during pregnancy.
Publisher: Informa UK Limited
Date: 07-2019
DOI: 10.2147/COPD.S208428
Publisher: Springer Singapore
Date: 2020
Publisher: American Thoracic Society
Date: 05-2012
DOI: 10.1164/AJRCCM-CONFERENCE.2012.185.1_MEETINGABSTRACTS.A2863
Publisher: American Thoracic Society
Date: 04-2009
DOI: 10.1164/AJRCCM-CONFERENCE.2009.179.1_MEETINGABSTRACTS.A2228
Publisher: BMJ
Date: 03-03-2012
DOI: 10.1136/THORAXJNL-2011-200160
Abstract: 20-30% of patients with asthma have neutrophilic airway inflammation and reduced responsiveness to steroid therapy. They often have chronic airway bacterial colonisation and Haemophilus influenzae is one of the most commonly isolated bacteria. The relationship between chronic airway colonisation and the development of steroid-resistant neutrophilic asthma is unclear. To investigate the relationship between H influenzae respiratory infection and neutrophilic asthma using mouse models of infection and ovalbumin (OVA)-induced allergic airways disease. BALB/c mice were intratracheally infected with H influenzae (day 10), intraperitoneally sensitised (day 0) and intranasally challenged (day 12-15) with OVA. Treatment groups were administered dexamethasone intranasally during OVA challenge. Infection, allergic airways disease, steroid sensitivity and immune responses were assessed (days 11, 16 and 21). The combination of H influenzae infection and allergic airways disease resulted in chronic lung infection that was detected on days 11, 16 and 21 (21, 26 and 31 days after infection). Neutrophilic allergic airways disease and T helper 17 cell development were induced, which did not require active infection. Importantly, all features of neutrophilic allergic airways disease were steroid resistant. Toll-like receptor 4 expression and activation of phagocytes was reduced, but most significantly the influx and/or development of phagocytosing neutrophils and macrophages into the airways was inhibited. The combination of infection and allergic airways disease promotes bacterial persistence, leading to the development of a phenotype similar to steroid-resistant neutrophilic asthma and which may result from dysfunction in innate immune cells. This indicates that targeting bacterial infection in steroid-resistant asthma may have therapeutic benefit.
Publisher: Elsevier
Date: 2019
Publisher: Hindawi Limited
Date: 29-11-2020
DOI: 10.1111/JFBC.13572
Publisher: Akademiai Kiado Zrt.
Date: 03-2017
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.BIOPHA.2018.05.045
Abstract: The Special AT-rich Sequence Binding Protein 1 (SATB1) is a chromatin organiser and transcription factor which regulates numerous cellular processes such as differentiation, proliferation and apoptosis through effects on gene expression. SATB1 undergoes various post-translational modifications, which determine its interaction with co-activators and co-repressors to induce regulation of gene transcription. SATB1 is an identified oncogene, its increased expression is associated with poor prognosis in many cancers. This paper provides a review on SATB1-mediated immune responses and on its target genes in the context of tumorigenesis and tumour progression. Specifically, we discuss the role of SATB1 in tumour immunity, Epithelial to Mesenchymal Transition (EMT), metastasis and multidrug resistance. Therapeutic targeting of aberrant SATB1 may be an important strategy in the treatment of cancer.
Publisher: European Respiratory Society
Date: 07-03-2019
Publisher: Springer Science and Business Media LLC
Date: 11-2018
DOI: 10.1007/S40265-018-1001-8
Abstract: Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship.
Publisher: Future Medicine Ltd
Date: 11-2021
Publisher: American Thoracic Society
Date: 05-2010
DOI: 10.1164/AJRCCM-CONFERENCE.2010.181.1_MEETINGABSTRACTS.A5603
Publisher: American Thoracic Society
Date: 15-01-2019
Publisher: Springer Science and Business Media LLC
Date: 14-06-2023
DOI: 10.1038/S41467-023-39174-1
Abstract: Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF gene name F3 ) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli , and S. aureus , with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Publisher: Informa UK Limited
Date: 05-11-2012
DOI: 10.1517/13543784.2013.732997
Abstract: Asthma is a major disease burden worldwide. Treatment with steroids and long acting β-agonists effectively manage symptoms in many patients but do not treat the underlying cause of disease and have serious side effects when used long term and in children. Therapies targeting the underlying causes of asthma are urgently needed. T helper type 2 (Th2) cells and the cytokines they release are clinically linked to the presentation of all forms of asthma. They are the primary drivers of mild to moderate and allergic asthma. They also play a pathogenetic role in exacerbations and more severe asthma though other factors are also involved. Much effort using animal models and human studies has been dedicated to the identification of the pathogenetic roles of these cells and cytokines and whether inhibition of their activity has therapeutic benefit in asthma. We discuss the current status of Th2 cytokine antagonists for the treatment of asthma. We also discuss the potential for targeting Th2-inducing cytokines, Th2 cell receptors and signaling as well as the use of Th2 cell antagonists, small interfering oligonucleotides, microRNAs, and combination therapies. Th2 antagonists may be most effective in particular asthma subtypes/endotypes where specific cytokines are known to be active through the analysis of biomarkers. Targeting common receptors and pathways used by these cytokines may have additional benefit. Animal models have been valuable in identifying therapeutic targets in asthma, however the results from such studies need to be carefully interpreted and applied to appropriately stratified patient cohorts in well-designed clinical studies and trials.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JACI.2016.04.038
Abstract: Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is h ered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.
Publisher: MDPI AG
Date: 08-03-2022
DOI: 10.3390/PHARMACEUTICS14030586
Abstract: Antibiotic resistance has become a threat to microbial therapies nowadays. The conventional approaches possess several limitations to combat microbial infections. Therefore, to overcome such complications, novel drug delivery systems have gained pharmaceutical scientists’ interest. Significant findings have validated the effectiveness of novel drug delivery systems such as polymeric nanoparticles, liposomes, metallic nanoparticles, dendrimers, and lipid-based nanoparticles against severe microbial infections and combating antimicrobial resistance. This review article comprises the specific mechanism of antibiotic resistance development in bacteria. In addition, the manuscript incorporated the advanced nanotechnological approaches with their mechanisms, including interaction with the bacterial cell wall, inhibition of biofilm formations, activation of innate and adaptive host immune response, generation of reactive oxygen species, and induction of intracellular effect to fight against antibiotic resistance. A section of this article demonstrated the findings related to the development of delivery systems. Lastly, the role of microfluidics in fighting antimicrobial resistance has been discussed. Overall, this review article is an amalgamation of various strategies to study the role of novel approaches and their mechanism to fight against the resistance developed to the antimicrobial therapies.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1038/MI.2013.29
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-04-2022
DOI: 10.1126/SCITRANSLMED.AAZ8454
Abstract: Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood s les collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3 + CD4 + T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1β and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.
Publisher: Wiley
Date: 22-05-2020
Publisher: American Society for Microbiology
Date: 2006
DOI: 10.1128/IAI.74.1.566-577.2006
Abstract: The gram-positive bacterium Listeria monocytogenes causes a life-threatening disease known as listeriosis. The mechanism by which L. monocytogenes invades mammalian cells is not fully understood, but the processes involved may provide targets to prevent and treat listeriosis. Here, for the first time, we have identified the insulin-like growth factor II receptor (IGFIIR also known as the cation-independent mannose 6-phosphate receptor CI M6PR or CD222) as a novel receptor for binding and invasion of Listeria species. Random peptide phage display was employed to select a peptide sequence by panning with immobilized L. monocytogenes cells this peptide sequence corresponds to a sequence within the mannose 6-phosphate binding site of the IGFIIR. All Listeria spp. specifically bound the labeled peptide but not a control peptide, which was demonstrated using fluorescence spectrophotometry and fluorescence-activated cell sorting. Further evidence for binding of the receptor by L. monocytogenes and L. innocua was provided by affinity purification of the bovine IGFIIR from fetal calf serum by use of magnetic beads coated with cell preparations of Listeria spp. as affinity matrices. Adherence to and invasion of mammalian cells by L. monocytogenes was significantly inhibited by both the synthetic peptide and mannose 6-phosphate but not by appropriate controls. These observations indicate a role for the IGFIIR in the adherence and invasion of L. monocytogenes of mammalian cells, perhaps in combination with known mechanisms. Ligation of IGFIIR by L. monocytogenes may be a novel mechanism that contributes to the regulation of infectivity, possibly in combination with other mechanisms.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Research Square Platform LLC
Date: 05-01-2022
DOI: 10.21203/RS.3.RS-1179181/V1
Abstract: Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. We tested a novel subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant, delivered to mice parenterally or mucosally. Both routes of vaccination induced substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generated anti-Spike IgA, increased nAb in the serum and airways, and increased lung CD4 + T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determined that TLR2 expression in either compartment facilitated early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells was essential for optimal lung-localised, antigen-specific responses. In a K18-hACE2 mice, vaccination provided complete protection against disease and sterilising lung immunity against SARS-CoV-2. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.
Publisher: Wiley
Date: 2019
DOI: 10.1002/CTI2.1084
Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti‐inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD. Here, we identify a novel protective role for TTP in CS‐induced experimental COPD using Zfp36 aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNA‐destabilising factor. TTP wild‐type ( Zfp36 +/+ ) and Zfp36 aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. After four days of CS exposure, Zfp36 aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild‐type controls. After eight weeks, Zfp36 aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema‐like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL (S) , and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS‐induced experimental COPD were ameliorated. Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-11-2021
DOI: 10.1126/SCITRANSLMED.AAV7223
Abstract: Inhibition of cigarette smoke–induced microRNA-21 suppresses chronic obstructive pulmonary disease through effects on a SATB1/S100A9/NF-κB axis.
Publisher: MDPI AG
Date: 13-09-2022
DOI: 10.3390/PROTEOMES10030033
Abstract: (1) Background: MALDI imaging is a technique that still largely depends on time of flight (TOF)-based instrument such as the Bruker UltrafleXtreme. While capable of performing targeted MS/MS, these instruments are unable to perform fragmentation while imaging a tissue section necessitating the reliance of MS1 values for peptide level identifications. With this premise in mind, we have developed a hybrid bioinformatic/image-based method for the identification and validation of viral biomarkers. (2) Methods: Formalin-Fixed Paraffin-Embedded (FFPE) mouse s les were sectioned, mounted and prepared for mass spectrometry imaging using our well-established methods. Peptide identification was achieved by first extracting confident images corresponding to theoretical viral peptides. Next, those masses were used to perform a Peptide Mmass Fingerprint (PMF) searched against known viral FASTA sequences against a background mouse FASTA database. Finally, a correlational analysis was performed with imaging data to confirm pixel-by-pixel colocalization and intensity of viral peptides. (3) Results: 14 viral peptides were successfully identified with significant PMF Scores and a correlational result of .79 confirming the presence of the virus and distinguishing it from the background mouse proteins. (4) Conclusions: this novel approach leverages the power of mass spectrometry imaging and provides confident identifications for viral proteins without requiring MS/MS using simple MALDI Time Of Flight/Time Of Flight (TOF/TOF) instrumentation.
Publisher: Oxford University Press (OUP)
Date: 11-2005
DOI: 10.1016/J.FEMSRE.2004.12.002
Abstract: Listeria monocytogenes is an important food-borne pathogen and is widely tested for in food, environmental and clinical s les. Identification traditionally involved culture methods based on selective enrichment and plating followed by the characterization of Listeria spp. based on colony morphology, sugar fermentation and haemolytic properties. These methods are the gold standard but they are lengthy and may not be suitable for testing of foods with short shelf lives. As a result more rapid tests were developed based on antibodies (ELISA) or molecular techniques (PCR or DNA hybridization). While these tests possess equal sensitivity, they are rapid and allow testing to be completed within 48 h. More recently, molecular methods were developed that target RNA rather than DNA, such as RT-PCR, real time PCR or nucleic acid based sequence lification (NASBA). These tests not only provide a measure of cell viability but they can also be used for quantitative analysis. In addition, a variety of tests are available for sub-species characterization, which are particularly useful in epidemiological investigations. Early typing methods differentiated isolates based on phenotypic markers, such as multilocus enzyme electrophoresis, phage typing and serotyping. These phenotypic typing methods are being replaced by molecular tests, which reflect genetic relationships between isolates and are more accurate. These new methods are currently mainly used in research but their considerable potential for routine testing in the future cannot be overlooked.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2017
DOI: 10.1007/S13346-016-0343-6
Abstract: The rapid advancement in the area of microRNAs (miRNAs) from discovery to their translation into therapeutic moieties reflects their significance as important regulators in the management of disease pathology. The miRNAs can potentially be a new class of drugs in the near future for the treatment of various lung diseases, but it lacks the current knowledge how these identified therapeutic moieties can be designed into an effective, patient complaint and targeted drug delivery system. miRNAs have characteristic features like small size and low molecular weight which makes them easily translated into an effective drug delivery system. In this review, we have summarised the concept of miRNAs and different approaches which can be employed to deliver miRNAs effectively and safely to the target cells including the challenges associated with their development in particular emphasis on pulmonary diseases. Such approaches will be of interest for both the biological and formulation scientists to understand and explore the new vistas in the area of miRNA delivery for pulmonary inflammatory diseases.
Publisher: Future Medicine Ltd
Date: 05-2022
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.BBI.2011.03.014
Abstract: Stressful events during the perinatal period in both humans and animals have long-term consequences for the development and function of physiological systems and susceptibility to disease in adulthood. One form of stress commonly experienced in the neonatal period is exposure to bacterial and viral infections. The current study investigated the effects of live Chlamydia muridarum bacterial infection at birth followed by re-infection in adulthood on hippoc al glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) and stress response outcomes. Within 24 h of birth, neonatal mice were infected intranasally with C. muridarum (400 inclusion-forming units [ifu]) or vehicle. At 42 days, mice were re-infected (100 ifu) and euthanized 10 days later. In males, infection in adulthood alone had the most impact on the parameters measured with significant increases in GR protein compared to adult infection alone and significant increases MR protein and circulating corticosterone compared to other treatment groups. Neonatal infection alone induced the largest alterations in the females with results showing reciprocal patterns for GR protein and TH protein. Perinatal infection resulted in a blunted response following adult infection for both males and females across all parameters. The present study demonstrates for the first time that males and females respond differently to infection based on the timing of the initial insult and that there is considerable sex differences in the hippoc al phenotypes that emerge in adulthood after neonatal infection.
Publisher: Wiley
Date: 09-11-2010
DOI: 10.1111/J.1365-2222.2010.03503.X
Abstract: Asthma is an inflammatory airway disease that is characterized by an influx of eosinophils to the lungs, mucus hypersecretion and T helper type 2 cytokine production. Recent dietary changes, including a decreased ω-3 polyunsaturated fatty acid (PUFA) intake, may have contributed to increased asthma rates and dietary supplementation with marine oil could have clinical benefits. To assess the effects of dietary supplementation with ω-3 PUFAs on allergic inflammation and lung function using a mouse model of ovalbumin (OVA)-induced allergic airway disease (AAD). BALB/c mice received a daily supplement of either fish oil (rich in ω-3 PUFA) or lyprinol (a complex mixture of various marine lipids plus vitamin E and olive oil) before and during AAD. The effects of supplementation on AAD were assessed. Lyprinol but not fish oil treatment reduced eosinophil influx into the bronchoalveolar lavage fluid, the lung tissue surrounding the airways and the blood, decreased mucus hypersecretion in the lung and reduced airway hyperresponsiveness (AHR). The effects of lyprinol were not associated with changes in serum IgG1 or IgG2a, or the release of IL-4, IL-5, IL-13 and IFN-γ. Lyprinol suppresses the development of allergic inflammation and AHR in AAD. The therapeutic potential of dietary supplementation with lyprinol for asthma warrants further investigation.
Publisher: Elsevier BV
Date: 2021
Publisher: Future Science Ltd
Date: 16-03-2020
Publisher: Oxford University Press (OUP)
Date: 12-01-2011
Abstract: BACKGROUND The precise effects of cigarette smoking on female fertility have not yet been clearly defined. We have used a mouse model that mimics human smoking and is able to control for variables that may confound clinical studies to assess the impact of chronic smoking on the quality of mouse oocytes. METHODS Mice received cigarette smoke directly to their lungs for 12 weeks. Lung tissue was analyzed for emphysematous changes and cumulus enclosed oocytes (CEOs) were recovered to study their quality. CEOs were in vitro matured, fixed and stained for chromatin and tubulin. Meiotic spindles, chromatin and the zona pellucida were all examined using confocal microscopy. RESULTS After 12 weeks of cigarette smoking, mice developed alveolar tissue damage that was determined by an increase in destructive index of the lung parenchyma. The numbers of oocytes recovered and the rates of oocyte maturation were not significantly different from non-smoking mice. However, oocytes from smoking mice had a significantly thicker zona pellucida along with shorter and wider meiotic spindles. Furthermore in total, almost a quarter of oocytes from smoking mice were abnormal as assessed by either errors in chromosomal congression or spindle shape. CONCLUSIONS We have used a novel model of inhalational cigarette smoking to show that chronic smoking has a detrimental effect on oocyte quality, and this can be observed even though oocytes are removed from the ovary and cultured in vitro.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.JNUTBIO.2009.12.003
Abstract: Allergic airways disease (AAD) is associated with an increased influx of eosinophils to the lungs, mucus hypersecretion and Th2 cytokine production. Dietary antioxidant supplementation may alter cytokine responses and thus allergic inflammation. Lycopene is a potent dietary antioxidant. The objective of this study was to investigate the effects of lycopene, on allergic inflammation, in a mouse model of AAD. BALB/c mice receiving lycopene supplement or control were intraperitoneally sensitised and intranasally challenged with ovalbumin (OVA) to induce AAD. The effect of supplementation on inflammatory cell influx into bronchoalveolar lavage fluid, lung tissue and blood, mucus-secreting cell numbers in the airways, draining lymph node OVA-specific cytokine release, serum IgG1 levels and lung function in AAD was assessed. Supplementation reduced eosinophilic infiltrates in the bronchoalveolar lavage fluid, lung tissue and blood, and mucus-secreting cell numbers in the airways. The OVA-specific release of Th2-associated cytokines IL-4 and IL-5 was also reduced. We conclude that supplementation with lycopene reduces allergic inflammation both in the lungs and systemically, by decreasing Th2 cytokine responses. Thus, lycopene supplementation may have a protective effect against asthma.
Publisher: Future Science Ltd
Date: 05-2020
Publisher: American Thoracic Society
Date: 07-2016
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.VACCINE.2005.07.104
Abstract: Chlamydia pneumoniae causes a range of respiratory infections including bronchitis, pharyngitis and pneumonia. Infection has also been implicated in exacerbation/initiation of asthma and chronic obstructive pulmonary disease (COPD) and may play a role in atherosclerosis and Alzheimer's disease. We have used a mouse model of Chlamydia respiratory infection to determine the effectiveness of intranasal (IN) and transcutaneous immunization (TCI) to prevent Chlamydia lung infection. Female BALB/c mice were immunized with chlamydial major outer membrane protein (MOMP) mixed with cholera toxin and CpG oligodeoxynucleotide adjuvants by either the IN or TCI routes. Serum and bronchoalveolar lavage (BAL) were collected for antibody analysis. Mononuclear cells from lung-draining lymph nodes were stimulated in vitro with MOMP and cytokine mRNA production determined by real time PCR. Animals were challenged with live Chlamydia and weighed daily following challenge. At day 10 (the peak of infection) animals were sacrificed and the numbers of recoverable Chlamydia in lungs determined by real time PCR. MOMP-specific antibody-secreting cells in lung tissues were also determined at day 10 post-infection. Both IN and TCI protected animals against weight loss compared to non-immunized controls with both immunized groups gaining weight by day 10-post challenge while controls had lost 6% of body weight. Both immunization protocols induced MOMP-specific IgG in serum and BAL while only IN immunization induced MOMP-specific IgA in BAL. Both immunization routes resulted in high numbers of MOMP-specific antibody-secreting cells in lung tissues (IN>TCI). Following in vitro re-stimulation of lung-draining lymph node cells with MOMP IFNgamma mRNA increased 20-fold in cells from IN immunized animals (compared to non-immunized controls) while IFNgamma levels increased 6- to 7-fold in TCI animals. Ten days post challenge non-immunized animals had >7,000 IFU in their lungs, IN immunized animals <50 IFU and TCI immunized animals <1,500 IFU. Thus, both intranasal and transcutaneous immunization protected mice against respiratory challenge with Chlamydia. The best protection was obtained following IN immunization and correlated with IFNgamma production by mononuclear cells in lung-draining LN and MOMP-specific IgA in BAL.
Publisher: Wiley
Date: 19-01-2017
DOI: 10.1111/RESP.12971
Abstract: There is currently enormous interest in studying the role of the microbiome in health and disease. Microbiome's role is increasingly being applied to respiratory diseases, in particular COPD, asthma, cystic fibrosis and bronchiectasis. The changes in respiratory microbiomes that occur in these diseases and how they are modified by environmental challenges such as cigarette smoke, air pollution and infection are being elucidated. There is also emerging evidence that gut microbiomes play a role in lung diseases through the modulation of systemic immune responses and can be modified by diet and antibiotic treatment. There are issues that are particular to the Asia-Pacific region involving diet and prevalence of specific respiratory diseases. Each of these issues is further complicated by the effects of ageing. The challenges now are to elucidate the cause and effect relationships between changes in microbiomes and respiratory diseases and how to translate these into new treatments and clinical care. Here we review the current understanding and progression in these areas.
Publisher: The American Association of Immunologists
Date: 05-2017
DOI: 10.4049/JIMMUNOL.198.SUPP.53.9
Abstract: CO2 produced by systemic cellular respiration is hydrated into carbonic acid (H2CO3) that dissociates into H+ and HCO3−. These are transported in the plasma to the lungs where HCO3− is converted back into H2CO3 and CO2 that are expelled through breathing. Evidence suggests that dysfunction of the mechanisms that govern these processes may result in the development of respiratory acidosis (RA) and the cardinal features of severe, steroid-resistant (SSR) asthma. Reduced lung function, which occurs in SSR asthma, impairs removal of volatile H2CO3 and CO2, resulting in acid accumulation and increased arterial PaCO2. Patients with severe asthma often develop complications from increased PaCO2, which skews the PaCO2/HCO3− ratio resulting in increased H+ concentration and reduced pH. We developed three mouse models of respiratory infection and ovalbumin-induced SSR allergic airways disease (SSRAAD) that are highly representative of SSR asthma in humans. We used these models to show a role for impaired homeostatic acid-base balance in SSR asthma. All three infections suppress the induction of the expression of the chloride (Cl−)/HCO− pump, Slc26a4, in the airway mucosa in AAD. Importantly, SSRAAD is associated with increased levels of free H+ ions in bronchoalveolar lavage fluid. Administration of Slc26a4-specific siRNA in steroid-sensitive AAD, which mimics the effect of decreased Slc26a4 responses in SSRAAD, induced RA and steroid-resistant airway inflammation and AHR. Importantly, treatment of RA with NaHCO3 during infection-induced SSRAAD suppressed steroid-resistant AHR. Thus, we have identified a previously unrecognised role for deficient Slc26a4 responses that result in the development of RA and the pathogenesis of SSRAAD.
Publisher: Informa UK Limited
Date: 06-02-2011
DOI: 10.3109/10253890.2010.532576
Abstract: During the perinatal period, the developing brain is sensitive to environmental events. Deleterious programing resulting from infection, dietary restriction, or psychological stress has been observed and affects adult immune and endocrine systems as well as behavior. In this study, we determined whether neonatal infection permanently alters immune and glucocorticoid receptor signaling pathways in the adult hippoc us. A Chlamydia muridarum respiratory infection was induced in male and female mice at birth. Mice were allowed to recover and microarray analysis was conducted on RNA from adult hippoc al tissue. In males, neonatal infection induced an up-regulation of genes associated with cellular development, nervous system development and function, such as cyclin-dependent kinase inhibitor 1A. After neonatal infection, adult females exhibited a T-helper 2 immune bias with genes such as major histocompatibility complex, class II, DQ beta 1 up-regulated. Expression of prolactin, vasopressin, hypocretin, corticotrophin-releasing hormone-binding protein, and oxytocin were confirmed by quantitative real-time polymerase chain reaction. This study shows that neonatal infection differentially alters the gene expression profiles of both female and male mice along immune and neuroendocrine pathways.
Publisher: Hindawi Limited
Date: 14-10-2022
DOI: 10.1111/JFBC.14445
Abstract: Nutraceuticals have emerged as potential compounds to attenuate the COVID-19 complications. Precisely, these food additives strengthen the overall COVID treatment and enhance the immunity of a person. Such compounds have been used at a large scale, in almost every household due to their better affordability and easy access. Therefore, current research is focused on developing newer advanced formulations from potential drug candidates including nutraceuticals with desirable properties viz, affordability, ease of availability, ease of administration, stability under room temperature, and potentially longer shelf-lives. As such, various nutraceutical-based products such as compounds could be promising agents for effectively managing COVID-19 symptoms and complications. Most importantly, regular consumption of such nutraceuticals has been shown to boost the immune system and prevent viral infections. Nutraceuticals such as vitamins, amino acids, flavonoids like curcumin, and probiotics have been studied for their role in the prevention of COVID-19 symptoms such as fever, pain, malaise, and dry cough. In this review, we have critically reviewed the potential of various nutraceutical-based therapeutics for the management of COVID-19. We searched the information relevant to our topic from search engines such as PubMed and Scopus using COVID-19, nutraceuticals, probiotics, and vitamins as a keyword. Any scientific literature published in a language other than English was excluded. PRACTICAL APPLICATIONS: Nutraceuticals possess both nutritional values and medicinal properties. They can aid in the prevention and treatment of diseases, as well as promote physical health and the immune system, normalizing body functions, and improving longevity. Recently, nutraceuticals such as probiotics, vitamins, polyunsaturated fatty acids, trace minerals, and medicinal plants have attracted considerable attention and are widely regarded as potential alternatives to current therapeutic options for the effective management of various diseases, including COVID-19.
Publisher: Wiley
Date: 18-01-2016
DOI: 10.1111/RESP.12734
Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and inflammation. Airway bacterial colonization is increased in COPD however, the role of potentially pathogenic and non-pathogenic bacteria in the pathogenesis of disease is unclear. This study characterized the presence of bacteria in a well-characterized cohort of adults with COPD and healthy controls. Adults with COPD (n = 70) and healthy controls (n = 51) underwent clinical assessment and sputum induction. Sputum was dispersed, and total and differential cell counts were performed. Bacteria were cultured, identified and enumerated. Supernatants were assessed for neutrophil elastase (NE) and IL-1β. Common respiratory pathogens were also determined using real-time PCR. Participants with COPD had a typical neutrophilic inflammatory profile. The total load of bacteria was increased in COPD and was associated with poorer respiratory health status, as measured by the St George's Respiratory Questionnaire (Spearman's r = 0.336, P = 0.013). Significantly lower levels of culturable Bacillus species were identified compared with healthy controls. PCR analyses revealed increased rates of detection of potentially pathogenic bacteria with Haemophilus influenzae detection associated with higher sputum levels of NE and IL-1β, while Streptococcus pneumoniae was more common in male ex-smokers with emphysema and a deficit in diffusion capacity. Non-pathogenic and pathogenic bacteria were altered in the sputum of patients with COPD. These observations highlight the potential to identify treatment and management strategies that both target specific bacterial pathogens and restore the microbial balance, which may lead to reductions in inflammation and subsequent improvements in lung health.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Bentham Science Publishers Ltd.
Date: 30-08-2017
DOI: 10.2174/1381612823666170329150201
Abstract: Disseminated metastatic cancer requires insistent management owing to its reduced responsiveness for chemotherapeutic agents, toxicity to normal cells consequently lower survival rate and h ered quality of life of patients. Dendrimer mediated cancer therapy is advantageous over conventional chemotherapy, radiotherapy and surgical resection due to reduced systemic toxicity, and molecular level cell injury to cancerous mass, for an appreciable survival of the subject. Recently used dendrimer mediated nanotechnology for oncology aims to conquer these challenges. Dendrimers based nano-constructs are having architectures comparable to that of biological vesicles present in the human body. Operating with dendrimer technology, proffers the exclusive and novel strategies with numerous applications in cancer management involving diagnostics, therapeutics, imaging, and prognostics by sub-molecular interactions. Dendrimers are designed to acquire the benefits of the malignant tumor morphology and characteristics, i.e. leaky vasculature of tumor, expression of specific cell surface antigen, and rapid proliferation. Dendrimers mediated targeted therapy recommends innovatory function equally in diagnostics (imaging, immune-detection) as well as chemotherapy. Currently, dendrimers as nanomedicine has offered a strong assurance and advancement in drastically varying approaches towards cancer imaging and treatment. The present review discusses different approaches for cancer diagnosis and treatment such as, targeted and control therapy, photodynamic therapy, photo-thermal therapy, gene therapy, antiangiogenics therapy, radiotherapy etc.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2022
DOI: 10.1038/S41467-022-34297-3
Abstract: Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. Here, we report testing of a subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant (Pam 2 Cys), delivered to mice parenterally or mucosally. Both routes of vaccination induce substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generates anti-Spike IgA, increases nAb in the serum and airways, and increases lung CD4 + T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determine that TLR2 expression in either compartment facilitates early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells is essential for optimal lung-localised, antigen-specific responses. In K18-hACE2 mice, vaccination provides complete protection against disease and sterilising lung immunity against SARS-CoV-2, with a short-term non-specific protective effect from mucosal Pam 2 Cys alone. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.
Publisher: Wiley
Date: 17-10-2012
DOI: 10.1002/DEV.20615
Abstract: The current study investigated the effects of neonatal infection with Chlamydia muridarum bacteria on glucocorticoid (GR) and mineralocorticoid (MR) receptors in the adult mouse hippoc us. In male adults infected at birth, circulating corticosterone was significantly increased when compared to same sex controls while neonatal infection resulted in female adults with significantly increased GR mRNA compared to same sex controls. When comparing males and females after neonatal infection, males had significantly less GR protein than females. Interestingly, after control treatment, males had significantly more GR mRNA, MR mRNA, and GR protein with significantly lower corticosterone than females. Neonatal respiratory infection significantly impacts adult hippoc al GR and MR, and circulating corticosterone in a sex-specific manner potentially altering stress responsivity.
Publisher: eLife Sciences Publications, Ltd
Date: 14-02-2017
DOI: 10.7554/ELIFE.20444
Abstract: Influenza virus infections have a significant impact on global human health. In iduals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.
Publisher: MDPI AG
Date: 25-11-2021
DOI: 10.3390/PHARMACEUTICS13122008
Abstract: Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep–wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of the circadian rhythm could alter normal lung function. Chronotherapy is a type of therapy provided at specific time intervals based on an in idual’s circadian rhythm. This would allow the drug to show optimum action, and thereby modulate its pharmacokinetics to lessen unwanted or unintended effects. In this review, we deliberated on the recent advances employed in chrono-targeted therapeutics for chronic respiratory diseases.
Publisher: European Respiratory Society
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 07-07-2016
Publisher: Bentham Science Publishers Ltd.
Date: 02-12-2020
DOI: 10.2174/1871530320666200428113051
Abstract: Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Publisher: Frontiers Media SA
Date: 06-02-2018
Publisher: Begell House
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 03-10-2017
Abstract: The microbiota is vital for the development of the immune system and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the respiratory tract and the gut have recently been linked to alterations in immune responses and to disease development in the lungs. In this Opinion article, we review the microbial species that are usually found in healthy gastrointestinal and respiratory tracts, their dysbiosis in disease and interactions with the gut-lung axis. Although the gut-lung axis is only beginning to be understood, emerging evidence indicates that there is potential for manipulation of the gut microbiota in the treatment of lung diseases.
Publisher: Public Library of Science (PLoS)
Date: 08-2012
Publisher: Public Library of Science (PLoS)
Date: 22-08-2014
Publisher: MDPI AG
Date: 12-07-2021
Abstract: Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the offspring. We investigated the association between ambient air pollutants during pregnancy and cell populations in cord blood from babies born to mothers with asthma enrolled in the Breathing for Life Trial. For each patient (n = 91), daily mean ambient air pollutant levels were extracted during their entire pregnancy for sulfur dioxide (SO2), nitric oxide, nitrogen dioxide, carbon monoxide, ozone, particulate matter μm (PM10) or .5 μm (PM2.5), humidity, and temperature. Ninety-one cord blood s les were collected, stained, and assessed using fluorescence-activated cell sorting (FACS). Principal Component (PC) analyses of both air pollutants and cell types with linear regression were employed to define associations. Considering risk factors and correlations between PCs, only one PC from air pollutants and two from cell types were statistically significant. PCs from air pollutants were characterized by higher PM2.5 and lower SO2 levels. PCs from cell types were characterized by high numbers of CD8 T cells, low numbers of CD4 T cells, and by high numbers of plasmacytoid dendritic cells (pDC) and low numbers of myeloid DCs (mDCs). PM2.5 levels during pregnancy were significantly associated with high numbers of pDCs (p = 0.006), and SO2 with high numbers of CD8 T cells (p = 0.002) and low numbers of CD4 T cells (p = 0.011) and mDCs (p = 4.43 × 10−6) in cord blood. These data suggest that ambient SO2 and PM2.5 exposure are associated with shifts in cord blood cell types that are known to play significant roles in inflammatory respiratory disease in childhood.
Publisher: Public Library of Science (PLoS)
Date: 24-06-2015
Publisher: MDPI AG
Date: 16-09-2022
DOI: 10.3390/NU14183828
Abstract: Chronic inflammation of the respiratory tract is one of the most concerning public health issues, as it can lead to chronic respiratory diseases (CRDs), some of which are more detrimental than others. Chronic respiratory diseases include chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and pulmonary fibrosis. The conventional drug therapies for the management and treatment of CRDs only address the symptoms and fail to reverse or recover the chronic-inflammation-mediated structural and functional damage of the respiratory tract. In addition, the low efficacy and adverse effects of these drugs have directed the attention of researchers towards nutraceuticals in search of potential treatment strategies that can not only ameliorate CRD symptoms but also can repair and reverse inflammatory damage. Hence, there is a growing interest toward investigating the medicinal benefits of nutraceuticals, such as rutin, curcumin, zerumbone, and others. Nutraceuticals carry many nutritional and therapeutic properties, including anti-inflammatory, antioxidant, anticancer, antidiabetic, and anti-obesity properties, and usually do not have as many adverse effects, as they are naturally sourced. Recently, the use of nanoparticles has also been increasingly studied for the nano drug delivery of these nutraceuticals. The discrete size of nanoparticles holds great potential for the level of permeability that can be achieved when transporting these nutraceutical compounds. This review is aimed to provide an understanding of the use of nutraceuticals in combination with nanoparticles against CRDs and their mechanisms involved in slowing down or reversing the progression of CRDs by inhibiting pro-inflammatory signaling pathways.
Publisher: European Respiratory Society (ERS)
Date: 10-2018
DOI: 10.1183/23120541.00031-2018
Abstract: Long-term, low-dose azithromycin reduces exacerbation frequency in chronic obstructive pulmonary disease (COPD), yet the mechanism remains unclear. This study characterised genome-wide gene expression changes in patients with neutrophilic COPD following long-term, low-dose azithromycin treatment. Patients with neutrophilic COPD ( % or ×10 4 cells per mL sputum neutrophils) were randomised to receive either azithromycin or placebo for 12 weeks. Sputum and blood were obtained before and after 12 weeks of treatment. Gene expression was defined using microarrays. Networks were analysed using the Search Tool for the Retrieval of Interacting Gene database. In sputum, 403 genes were differentially expressed following azithromycin treatment (171 downregulated and 232 upregulated), and three following placebo treatment (one downregulated and two upregulated) compared to baseline (adjusted p .05 by paired t-test, fold-change .5). In blood, 138 genes were differentially expressed with azithromycin (121 downregulated and 17 upregulated), and zero with placebo compared to baseline (adjusted p .05 by paired t-test, fold-change .3). Network analysis revealed one key network in both sputum (14 genes) and blood (46 genes), involving interferon-stimulated genes, human leukocyte antigens and genes regulating T-cell responses. Long-term, low-dose azithromycin is associated with downregulation of genes regulating antigen presentation, interferon and T-cell responses, and numerous inflammatory pathways in the airways and blood of neutrophilic COPD patients.
Publisher: American Thoracic Society
Date: 15-01-2010
Publisher: Wiley
Date: 25-05-2015
DOI: 10.1002/ART.39041
Abstract: Chlamydia trachomatis is a sexually transmitted obligate intracellular pathogen that causes inflammatory reactive arthritis, spondylitis, psoriasiform dermatitis, and conjunctivitis in some in iduals after genital infection. The immunologic basis for this inflammatory response in susceptible hosts is poorly understood. As ZAP‐70 W163C –mutant BALB/c (SKG) mice are susceptible to spondylo‐arthritis after systemic exposure to microbial β‐glucan, we undertook the present study to compare responses to infection with Chlamydia muridarum in SKG mice and BALB/c mice. After genital or respiratory infection with C muridarum , conjunctivitis and arthritis were assessed clinically, and eye, skin, and joint specimens were analyzed histologically. Chlamydial major outer membrane protein antigen–specific responses were assessed in splenocytes. Treg cells were depleted from FoxP3‐DTR BALB/c or SKG mice, and chlamydial DNA was quantified by polymerase chain reaction. Five weeks after vaginal infection with live C muridarum , arthritis, spondylitis, and psoriasiform dermatitis developed in female SKG mice, but not in BALB/c mice. Inflammatory bowel disease did not occur in mice of either strain. The severity of inflammatory disease was correlated with C muridarum inoculum size and vaginal burden postinoculation. Treatment with combination antibiotics starting 1 day postinoculation prevented disease. Chlamydial antigen was present in macrophages and spread from the infection site to lymphoid organs and peripheral tissue. In response to chlamydial antigen, production of interferon‐γ and interleukin‐17 was impaired in T cells from SKG mice but tumor necrosis factor (TNF) responses were exaggerated, compared to findings in T cells from BALB/c mice. Unlike previous observations in arthritis triggered by β‐glucan, no autoantibodies developed. Accelerated disease triggered by depletion of Treg cells was TNF dependent. In the susceptible SKG strain, Chlamydia ‐induced reactive arthritis develops as a result of deficient intracellular pathogen control, with antigen‐specific TNF production upon dissemination of antigen, and TNF‐dependent inflammatory disease.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1038/MI.2012.99
Abstract: Deleterious responses to pathogens during infancy may contribute to infection and associated asthma. Chlamydia respiratory infections in early life are common causes of pneumonia and lead to reduced lung function and asthma. We investigated the role of interleukin-13 (IL-13) in promoting early-life Chlamydia respiratory infection, infection-induced airway hyperresponsiveness (AHR), and severe allergic airway disease (AAD). Infected infant Il13(-/-) mice had reduced infection, inflammation, and mucus-secreting cell hyperplasia. Surprisingly, infection of wild-type (WT) mice did not increase IL-13 production but reduced IL-13Rα2 decoy receptor levels compared with sham-inoculated controls. Infection of WT but not Il13(-/-) mice induced persistent AHR. Infection and associated pathology were restored in infected Il13(-/-) mice by reconstitution with IL-13. Stat6(-/-) mice were also largely protected. Neutralization of IL-13 during infection prevented subsequent infection-induced severe AAD. Thus, early-life Chlamydia respiratory infection reduces IL-13Rα2 production, which may enhance the effects of constitutive IL-13 and promote more severe infection, persistent AHR, and AAD.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1038/MI.2013.65
Abstract: Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease.
Publisher: The American Association of Immunologists
Date: 05-2017
DOI: 10.4049/JIMMUNOL.198.SUPP.131.5
Abstract: There is a critical window in early-life where the lung is still maturing and susceptible to infection. Indeed, severe respiratory infections in early-life are a risk factor for the development of chronic lung diseases. The aim of this study was to identify the mechanisms involved. Neonatal wild-type (WT), TLR2 deficient (−/−), IL-13−/−, MyD88−/− and STAT6−/− mice were infected with the natural mouse bacterial pathogen Chlamydia muridarum, as a model of severe respiratory tract infection in early-life. In some experiments WT mice were treated with miR-21 antagomirs, PI3K inhibitors, or relevant controls during early-life infection. The impact of targeting these specific immune molecules during early-life on infection-induced impairment of lung function and structure were assessed. Neonatal Chlamydia respiratory infection increased TLR2, IL-13-receptor, miR-21 and PI3K expression and/or activity in the lung. TLR2 signalling induced IL-13-receptor expression, IL-13 signalling induced miR-21 expression and miR-21 increased PI3K activity. TLR2 signalling also increased IL-13+ ILC2s in the lung. TLR2−/− and IL-13−/− mice were protected against infection-induced airway hyperresponsiveness (AHR), but not emphysema-like alveolar enlargement. This TLR2/IL-13 mediated phenotype was independent of MyD88, but dependent on STAT6. Specific targeting of miR-21 prevented AHR but not emphysema. Pan-PI3K inhibition did not affect AHR, but protected against emphysema. Interestingly, early-life infection-induced AHR was steroid insensitive. This study identifies a novel signalling network that may be targeted for the prevention of the long-term deleterious effects of early-life infection on lung function and structure.
Publisher: MDPI AG
Date: 21-04-2023
Abstract: Oxidative stress is a major hallmark of COPD, contributing to inflammatory signaling, corticosteroid resistance, DNA damage, and accelerated lung aging and cellular senescence. Evidence suggests that oxidative damage is not solely due to exogenous exposure to inhaled irritants, but also endogenous sources of oxidants in the form of reactive oxygen species (ROS). Mitochondria, the major producers of ROS, exhibit impaired structure and function in COPD, resulting in reduced oxidative capacity and excessive ROS production. Antioxidants have been shown to protect against ROS-induced oxidative damage in COPD, by reducing ROS levels, reducing inflammation, and protecting against the development of emphysema. However, currently available antioxidants are not routinely used in the management of COPD, suggesting the need for more effective antioxidant agents. In recent years, a number of mitochondria-targeted antioxidant (MTA) compounds have been developed that are capable of crossing the mitochondria lipid bilayer, offering a more targeted approach to reducing ROS at its source. In particular, MTAs have been shown to illicit greater protective effects compared to non-targeted, cellular antioxidants by further reducing apoptosis and offering greater protection against mtDNA damage, suggesting they are promising therapeutic agents for the treatment of COPD. Here, we review evidence for the therapeutic potential of MTAs as a treatment for chronic lung disease and discuss current challenges and future directions.
Publisher: American Thoracic Society
Date: 05-2011
DOI: 10.1164/AJRCCM-CONFERENCE.2011.183.1_MEETINGABSTRACTS.A4348
Publisher: MDPI AG
Date: 22-02-2022
DOI: 10.3390/IJMS23052408
Abstract: Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.
Publisher: Wiley
Date: 12-10-2017
DOI: 10.1111/RESP.12908
Abstract: COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2014
Publisher: Informa UK Limited
Date: 29-09-2020
Publisher: Oxford University Press (OUP)
Date: 10-2007
Publisher: MDPI AG
Date: 31-05-2023
DOI: 10.3390/JCM12113791
Abstract: Chronic obstructive pulmonary disease (COPD) is significant cause of morbidity and mortality worldwide. There is mounting evidence suggesting that COPD patients are at increased risk of severe COVID-19 outcomes however, it remains unclear whether they are more susceptible to acquiring SARS-CoV-2 infection. In this comprehensive review, we aim to provide an up-to-date perspective of the intricate relationship between COPD and COVID-19. We conducted a thorough review of the literature to examine the evidence regarding the susceptibility of COPD patients to COVID-19 infection and the severity of their disease outcomes. While most studies have found that pre-existing COPD is associated with worse COVID-19 outcomes, some have yielded conflicting results. We also discuss confounding factors such as cigarette smoking, inhaled corticosteroids, and socioeconomic and genetic factors that may influence this association. Furthermore, we review acute COVID-19 management, treatment, rehabilitation, and recovery in COPD patients and how public health measures impact their care. In conclusion, while the association between COPD and COVID-19 is complex and requires further investigation, this review highlights the need for careful management of COPD patients during the pandemic to minimize the risk of severe COVID-19 outcomes.
Publisher: Future Science Ltd
Date: 11-2020
Abstract: Aim: In the present study boswellic acids-loaded chitosan nanoparticles were synthesized using ionic gelation technique. The influence of independent variables were studied and optimized on dependent variables using central composite design. Methodology & results: The designed nanoparticles were observed spherical in shape with an average size of 67.5–187.2 nm and have also shown an excellent entrapment efficiency (80.06 ± 0.48). The cytotoxicity assay revealed enhanced cytotoxicity for drug-loaded nanoparticles in contrast to the free drug having an IC 50 value of 17.29 and 29.59 μM, respectively. Flow cytometry confirmed that treatment of cells with 40 μg/ml had arrested 22.75 ± 0.3% at SubG 0 phase of the cell cycle when compared with untreated A459 cells. The observed results justified the boswellic acids-loaded chitosan nanoparticles were effective due to greater cellular uptake, sustained intercellular drug retention and enhanced antiproliferative effect by inducing apoptosis.
Publisher: American Society for Clinical Investigation
Date: 16-05-2019
Publisher: The American Association of Immunologists
Date: 04-2009
DOI: 10.4049/JIMMUNOL.182.SUPP.79.5
Abstract: Chlamydial lung infections are associated with asthma but it is unknown how these Th1-inducing infections influence Th2-mediated asthma. We investigated the effect of current and resolved chlamydial infection on the development of hallmark features of asthma using a murine model of ovalbumin (Ova)-induced AAD. BALB/c mice were infected with Chlamydia and had either resolved or current respiratory infection at the time of sensitization to Ova. The effect of infection on AAD was compared with un-infected or non-allergic controls. Current, but not resolved, infection attenuated hallmark features of eosinophilic AAD pulmonary eosinophil influx, T cell production of IL-5, mucus secreting cell (MSC) hyperplasia and airways hyper-responsiveness (AHR). Importantly, while current infection suppressed Th2-mediated AAD, robust Ova-specific IFN-γ release from T cells and allergen-driven neutrophilic inflammation were induced. This neutrophilic phenotype correlated with increased pulmonary expression of IL-12 and IL-17 and suppression of thymus and activation-related chemokine (TARC). Inhibition of neutrophil and macrophage chemotaxis into the lungs during current infection reversed neutrophilic inflammation and IFN-γ production in AAD and removed the attenuating effect of infection on MSC hyperplasia and AHR. These changes correlated with decreased IL-12 and IL-17 expression, increased TARC and altered antigen presenting cell function. Ongoing chlamydial respiratory infections modify key allergen-specific immune responses in AAD with the composition of cellular inflammatory responses to infection crucial in determining the outcome of allergic phenotype. Supported by the NHMRC
Publisher: Springer Science and Business Media LLC
Date: 07-02-2019
Publisher: Wiley
Date: 30-03-2020
DOI: 10.1002/PATH.5401
Publisher: American Society for Microbiology
Date: 02-2004
DOI: 10.1128/IAI.72.2.1019-1028.2004
Abstract: Chlamydia trachomatis is a pathogen of the genital tract and ocular epithelium. Infection is established by the binding of the metabolically inert elementary body (EB) to epithelial cells. These are taken up by endocytosis into a membrane-bound vesicle termed an inclusion. The inclusion avoids fusion with host lysosomes, and the EBs differentiate into the metabolically active reticulate body (RB), which replicates by binary fission within the protected environment of the inclusion. During the extracellular EB stage of the C. trachomatis life cycle, antibody present in genital tract or ocular secretions can inhibit infection both in vivo and in tissue culture. The RB, residing within the intracellular inclusion, is not accessible to antibody, and resolution of infection at this stage requires a cell-mediated immune response mediated by gamma interferon-secreting Th1 cells. Thus, an ideal vaccine to protect against C. trachomatis genital tract infection should induce both antibody (immunoglobulin A [IgA] and IgG) responses in mucosal secretions to prevent infection by chlamydial EB and a strong Th1 response to limit ascending infection to the uterus and fallopian tubes. In the present study we show that transcutaneous immunization with major outer membrane protein (MOMP) in combination with both cholera toxin and CpG oligodeoxynucleotides elicits MOMP-specific IgG and IgA in vaginal and uterine lavage fluid, MOMP-specific IgG in serum, and gamma interferon-secreting T cells in reproductive tract-draining caudal and lumbar lymph nodes. This immunization protocol resulted in enhanced clearance of C. muridarum ( C. trachomatis , mouse pneumonitis strain) following intravaginal challenge of BALB/c mice.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.BIOCEL.2016.07.030
Abstract: Corticosteroids are effective anti-inflammatory therapies widely utilized in chronic respiratory diseases. But these medicines can lose their efficacy during respiratory infection resulting in disease exacerbation. Further in vitro research is required to understand how infection worsens lung function control in order to advance therapeutic options to treat infectious exacerbation in the future. In this study, we utilize a cellular model of bacterial exacerbation where we pretreat A549 lung epithelial cells with the synthetic bacterial lipoprotein Pam3CSK4 (a TLR2 ligand) to mimic bacterial infection and tumor necrosis factor α (TNFα) to simulate inflammation. Under these conditions, Pam3CSK4 induces corticosteroid insensitivity demonstrated by substantially reduced ability of the corticosteroid dexamethasone to repress TNFα-induced interleukin 6 secretion. We then explored the molecular mechanism responsible and found that corticosteroid insensitivity induced by bacterial mimics was not due to altered translocation of the glucocorticoid receptor into the nucleus, nor an impact on the NF-κB pathway. Moreover, Pam3CSK4 did not affect corticosteroid-induced upregulation of anti-inflammatory MAPK deactivating phosphatase-MKP-1. However, Pam3CSK4 can induce oxidative stress and we show that a proportion of the MKP-1 produced in response to corticosteroid in the context of TLR2 ligation was rendered inactive by oxidation. Thus to combat inflammation in the context of bacterial exacerbation we sought to discover effective strategies that bypassed this road-block. We show for the first time that known (FTY720) and novel (theophylline) activators of the phosphatase PP2A can serve as non-steroidal anti-inflammatory alternatives and/or corticosteroid-sparing approaches in respiratory inflammation where corticosteroid insensitivity exists.
Publisher: MDPI AG
Date: 21-12-2021
Abstract: The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause–effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an in idual entity and direct future research towards it.
Publisher: Future Science Ltd
Date: 03-2021
Abstract: Aim: In the present study, the inhibitory potential of rutin-loaded liquid crystalline nanoparticles (LCNs) on oxidative stress was determined in human bronchial epithelial cells (BEAS-2B) by analysing the expression levels of different antioxidant (NADPH quinine oxidoreductase-1 ( NQO1) γ-glutamyl cysteine synthetase catalytic subunit ( GCLC)) and pro-oxidant (NADPH oxidase (Nox)-4 Nox2B) genes. Results: Our findings revealed that the rutin-loaded LCNs inhibited the genes, namely Nox2B and Nox4, which caused oxidative stress. In addition, these nanoparticles demonstrated an upregulation in the expression of the antioxidant genes Gclc and Nqo-1 in a dose-dependent manner. Conclusion: The study indicates the promising potential of rutin-loaded LCNs as an effective treatment strategy in patients with high oxidant loads in various respiratory diseases.
Publisher: Journal of Biological Methods
Date: 03-07-2017
Abstract: Bronchoalveolar lavage (BAL) is a simple, yet informative tool in understanding the immunopathology of various lung diseases via quantifying various inflammatory cells, cytokines and growth factors. At present, this traditional method is often blended with several robust and sophisticated molecular and biological techniques sustaining the significance and longevity of this technique. Crucially, the existence of slightly distinct approaches and variables employed at different laboratories around the globe in performing BAL aspiration indeed demands an utmost need to optimize and develop an effective, cost-effective and a reproducible technique. This mini review will be of importance to the biological translational scientist, particularly respiratory researchers in understanding the fundamentals and approaches to apply and consider with BAL aspiration techniques. This will ensure generating a meaningful and clinically relevant data which in turn accelerate the development of new and effective therapeutic moieties for major respiratory conditions.
Publisher: The American Association of Immunologists
Date: 15-04-2010
Abstract: Neutrophilic asthma is a prevalent, yet recently described phenotype of asthma. It is characterized by neutrophilic rather than eosinophilic airway inflammation and airways hyperresponsiveness (AHR) and may have an infectious origin. Chlamydial respiratory infections are associated with asthma, but how these Th1-inducing bacteria influence Th2-mediated asthma remains unknown. The effects of chlamydial infection on the development of asthma were investigated using a BALB/c mouse model of OVA-induced allergic airways disease (AAD). The effects of current and resolved Chlamydia muridarum infection during OVA sensitization on AAD were assessed and compared with uninfected and nonsensitized controls. Current, but not resolved, infection attenuated hallmark features of AAD: pulmonary eosinophil influx, T cell production of IL-5, mucus-secreting cell hyperplasia, and AHR. Current infection also induced robust OVA-driven neutrophilic inflammation and IFN-γ release from T cells. The phenotype of suppressed but persistent Th2 responses in association with enhanced neutrophilia is reminiscent of neutrophilic asthma. This phenotype was also characterized by increased pulmonary IL-12 and IL-17 expression and activation of APCs, as well as by reduced thymus- and activation-regulated chemokine. Inhibition of pulmonary neutrophil influx during infection blocked OVA-induced neutrophilic inflammation and T cell IFN-γ production and reversed the suppressive effects on mucus-secreting cell hyperplasia and AHR during AAD. These changes correlated with decreased IL-12 and IL-17 expression, increased thymus- and activation-regulated chemokine and altered APC activation. Blocking IFN-γ and IL-17 during OVA challenge had no effect. Thus, active chlamydial respiratory infection during sensitization enhances subsequent neutrophilic inflammation and Th1/Th17 responses during allergen exposure and may have a role in the pathogenesis of neutrophilic asthma.
Publisher: Springer Singapore
Date: 2018
DOI: 10.1007/978-981-13-1426-1_1
Abstract: Circular RNAs (cirRNAs) are long, noncoding endogenous RNA molecules and covalently closed continuous loop without 5'-3' polarity and polyadenylated tail which are largely concentrated in the nucleus. CirRNA regulates gene expression by modulating microRNAs and functions as potential biomarker. CirRNAs can translate in vivo to link between their expression and disease. They are resistant to RNA exonuclease and can convert to the linear RNA by microRNA which can then act as competitor to endogenous RNA. This chapter summarizes the evolutionary conservation and expression of cirRNAs, their identification, highlighting various computational approaches on cirRNA, and translation with a focus on the breakthroughs and the challenges in this new field.
Publisher: American Physiological Society
Date: 06-2018
DOI: 10.1152/AJPLUNG.00438.2017
Abstract: Obesity is an important risk factor for developing severe asthma. Dietary fatty acids, which are increased in sera of obese in iduals and after high-fat meals, activate the innate immune system and induce inflammation. This study investigated whether dietary fatty acids directly cause inflammation and/or synergize with obesity-induced cytokines in primary human pulmonary fibroblasts in vitro. Fibroblasts were challenged with BSA-conjugated fatty acids [ω-6 polyunsaturated fatty acids (PUFAs) and ω-3 PUFAs or saturated fatty acids (SFAs)], with or without TNF-α, and release of the proinflammatory cytokines, IL-6 and CXCL8, was measured. We found that the ω-6 PUFA arachidonic acid (AA), but not ω-3 PUFAs or SFAs, upregulates IL-6 and CXCL8 release. Combined AA and TNF-α challenge resulted in substantially greater cytokine release than either alone, demonstrating synergy. Synergistic upregulation of IL-6, but not CXCL8, was mainly mediated via cyclooxygenase (COX). Inhibition of p38 MAPK reduced CXCL8 release, induced by AA and TNF-α alone, but not in combination. Synergistic CXCL8 release, following AA and TNF-α challenge, was not medicated via a single signaling pathway (MEK1, JNK, phosphoinositide 3-kinase, and NF-κB) nor by hyperactivation of NF-κB or p38. To investigate if these findings occur in other airway cells, effects of AA in primary human airway smooth muscle (ASM) cells and human bronchial epithelial cells were also investigated. We found proinflammatory effects in ASM cells but not epithelial cells. This study suggests that diets rich in ω-6 PUFAs might promote airway inflammation via multiple pathways, including COX-dependent and -independent pathways, and in an obese person, may lead to more severe airway inflammation.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.ENVINT.2018.12.051
Abstract: The genotoxic, mutagenic and carcinogenic effects of polar polycyclic aromatic hydrocarbons (polar PAHs) are believed to surpass those of their parent PAHs however, their environmental and human health implications have been largely unexplored. Oxygenated PAHs (oxy-PAHs) is a critical class of polar PAHs associated with carcinogenic effects without enzymatic activation. They also cause an upsurge in reactive oxygen species (ROS) in living cells. This results in oxidative stress and other consequences, such as abnormal gene expressions, altered protein activities, mutagenesis, and carcinogenesis. Similarly, some nitrated PAHs (N-PAHs) are probable human carcinogens as classified by the International Agency for Research on Cancer (IARC). Heterocyclic PAHs (polar PAHs containing nitrogen, sulphur and oxygen atoms within the aromatic rings) have been shown to be potent endocrine disruptors, primarily through their estrogenic activities. Despite the high toxicity and enhanced environmental mobility of many polar PAHs, they have attracted only a little attention in risk assessment of contaminated sites. This may lead to underestimation of potential risks, and remediation end points. In this review, the toxicity of polar PAHs and their associated mechanisms of action, including their role in mutagenic, carcinogenic, developmental and teratogenic effects are critically discussed. This review suggests that polar PAHs could have serious toxicological effects on human health and should be considered during risk assessment of PAH-contaminated sites. The implications of not doing so were argued and critical knowledge gaps and future research requirements discussed.
Publisher: European Respiratory Society (ERS)
Date: 04-06-2010
DOI: 10.1183/09031936.00049510
Abstract: An inverse association exists between some bacterial infections and the prevalence of asthma. We investigated whether Streptococcus pneumoniae infection protects against asthma using mouse models of ovalbumin (OVA)-induced allergic airway disease (AAD). Mice were intratracheally infected or treated with killed S. pneumoniae before, during or after OVA sensitisation and subsequent challenge. The effects of S. pneumoniae on AAD were assessed. Infection or treatment with killed S. pneumoniae suppressed hallmark features of AAD, including antigen-specific T-helper cell (Th) type 2 cytokine and antibody responses, peripheral and pulmonary eosinophil accumulation, goblet cell hyperplasia, and airway hyperresponsiveness. The effect of infection on the development of specific features of AAD depended on the timing of infection relative to allergic sensitisation and challenge. Infection induced significant increases in regulatory T-cell (Treg) numbers in lymph nodes, which correlated with the degree of suppression of AAD. Tregs reduced T-cell proliferation and Th2 cytokine release. The suppressive effects of infection were reversed by anti-CD25 treatment. Respiratory infection or treatment with S. pneumoniae attenuates allergic immune responses and suppresses AAD. These effects may be mediated by S. pneumoniae-induced Tregs. This identifies the potential for the development of therapeutic agents for asthma from S. pneumoniae.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.RESP.2015.07.004
Abstract: Infants born very preterm are usually exposed to high oxygen concentrations but this may impair lung function in survivors in later life. However, the precise changes involved are poorly understood. We determined how neonatal hyperoxia alters lung function at mid-adulthood in mice. Neonatal C57BL/6J mice inhaled 65% oxygen (HE group) from birth for 7 days. They then breathed room air until 11 months of age (P11mo) these mice experienced growth restriction. Controls breathed only room air. To exclude the effects of growth restriction, a group of dams was rotated between hyperoxia and normoxia during the exposure period (HE+DR group). Lung function was measured at P11mo. HE mice had increased inspiratory capacity, work of breathing and tissue d ing. HE+DR mice had further increases in inspiratory capacity and work of breathing, and reduced FEV100/FVC. Total lung capacity was increased in HE+DR males. HE males had elevated responses to methacholine. Neonatal hyperoxia alters lung function at mid-adulthood, especially in males.
Publisher: MDPI AG
Date: 15-02-2023
DOI: 10.3390/COSMETICS10010034
Abstract: Apart from well-known respiratory symptoms, less frequent symptoms also appear as a direct result of COVID-19 infection, or as indirect effects of the recommended quarantine and related lifestyle changes. The impact of the COVID-19 pandemic on human skin is predominantly focused on in this article. Cutaneous manifestations, including redness, chilblain-like symptoms (COVID toes), hives or urticaria rash, water blisters, and fishing net-like red-blue patterns on the skin, may appear as accompanying or as systemic COVID-19 symptoms with potential lesions at different skin sites. These symptoms were related to skin phototypes and vitamin D deficiency. Moreover, Black, Asian, and minority ethnic origin patients are found to be more sensitive to COVID-19 infection than Caucasians because of vitamin D deficiency. The region of population with lighter skin phototypes have a significantly higher chance to develop cutaneous manifestations than population with dark skin. In addition, adverse effects, such as skin barrier damage and irritation, may also occur due to extensive personal protective equipment usage (e.g., masks, protective suits, and a few others) and predominately alcohol-based sanitizers. This manuscript covers various aspects of COVID-19 and its clinical skin manifestations.
Publisher: MDPI AG
Date: 14-12-2021
DOI: 10.3390/NU13124461
Abstract: Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.
Publisher: American Thoracic Society
Date: 04-2009
DOI: 10.1164/AJRCCM-CONFERENCE.2009.179.1_MEETINGABSTRACTS.A2230
Publisher: Public Library of Science (PLoS)
Date: 11-01-2016
Publisher: Wiley
Date: 12-10-2016
DOI: 10.1111/BPH.13573
Publisher: Future Science Ltd
Date: 06-2020
Publisher: Elsevier BV
Date: 08-2010
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.BIOPHA.2018.05.099
Abstract: Microbiome refers to an ecological community of various symbiotic and pathogenic microorganisms, which plays a crucial role in human health and disease. The concept of novel drug delivery systems particularly the vesicular drug delivery systems is gaining massive attention. This emerging technology has started expanding its horizons in the area of microbiome delivery. This mini-review highlights the role of vesicular systems such as nanoparticles, liposomes etc. as a host/carrier for the microbiome in targeting various diseases. This review will be of interest for both the biological and formulation scientists to understand and explore the new vistas in the area of vesicular delivery system as carrier for microbiome delivery.
Publisher: Public Library of Science (PLoS)
Date: 05-05-2011
Publisher: American Thoracic Society
Date: 03-2018
No related grants have been discovered for Philip Hansbro.