ORCID Profile
0000-0003-2355-8632
Current Organisations
University of New South Wales
,
Liverpool Hospital
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Publisher: Wiley
Date: 03-2008
DOI: 10.1111/J.1440-1746.2007.05287.X
Abstract: The observation that only a minority of heavy drinkers develop pancreatitis has prompted an intensive search for a trigger factor/cofactor/susceptibility factor that may precipitate a clinical attack. Putative susceptibility factors examined so far include diet, smoking, amount and type of alcohol consumed, the pattern of drinking and lipid intolerance. In addition, a range of inherited factors have been assessed including blood group antigens, human leukocyte antigen serotypes, alpha-1-antitrypsin phenotypes and several genotypes. The latter group comprises mutations olymorphisms in genes related to alcohol-metabolizing enzymes, detoxifying enzymes, pancreatic digestive enzymes, pancreatic enzyme inhibitors, cystic fibrosis and cytokines. Disappointingly, despite this concerted research effort, no clear association has been established between the above factors and alcoholic pancreatitis. Experimentally, the secretagogue cholecystokinin (CCK) has been investigated as a candidate 'trigger' for alcoholic pancreatitis. However, the clinical relevance of CCK as a trigger factor has to be questioned, as it is difficult to envisage a situation in humans where abnormally high levels of CCK would be released into the circulation to trigger pancreatitis in alcoholics. In contrast, bacterial endotoxemia is a candidate cofactor that does have relevance to the clinical situation. Plasma lipopolysaccharide (LPS, an endotoxin) levels are significantly higher in drinkers (either after chronic alcohol intake or a single binge) compared to non-drinkers. We have recently shown that alcohol-fed animals challenged with otherwise innocuous doses of LPS exhibit significant pancreatic injury. Moreover, repeated LPS exposure in alcohol-fed rats leads to progressive injury to the gland characterized by significant pancreatic fibrosis. These studies support the concept that endotoxin may be an important factor in the initiation and progression of alcoholic pancreatitis. Scope remains for further studies examining proteins related to cellular anti-oxidant defenses, minor cystic fibrosis (CF) mutations and trans-heterozygosity involving a combination of mutations of different genes (such as CFTR alterations combined with SPINK1 or PRSS1 variants), as potential triggers of alcoholic pancreatitis.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2016
DOI: 10.1038/BJC.2015.478
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.CANLET.2015.10.035
Abstract: Pancreatic stellate cells (PSCs) are responsible for producing the collagenous stroma in pancreatic cancer. Findings from the majority of in vitro and in vivo studies to date indicate that PSCs interact with cancer cells as well as with other cellular elements in the stroma including immune cells, endothelial cells and neuronal cells to set up a growth permissive microenvironment for pancreatic tumours. However, two recent studies reporting a protective effect of myofibroblasts in pancreatic cancer have served to remind researchers of the possibility that the role of PSCs in this disease may be context and time-dependent, such that any possible early protective role of PSCs is subverted in later stages by the ability of cancer cells to turn PSCs into cancer-promoting aides. This concept is supported by the development in recent years of several novel therapeutic approaches targeting the stroma that have been successfully applied in pre-clinical settings to inhibit disease progression. A multi-pronged approach aimed at tumour cells as well as stromal elements may be the key to achieving better clinical outcomes in patients with pancreatic cancer.
Publisher: Elsevier BV
Date: 06-1986
DOI: 10.1016/0006-2952(86)90736-7
Abstract: This investigation was performed to determine whether chronic ethanol feeding affects adipose tissue lipogenesis and glucose metabolism. Female Wistar rats were pair-fed nutritionally adequate liquid diets containing ethanol as 36% of energy or an isocaloric amount of carbohydrate for 3 weeks. Chronic ethanol feeding resulted in a depression of adipose tissue lipogenesis as assessed by labeled glucose incorporation into glyceride glycerol and glyceride fatty acids. Glucose oxidation was also impaired after chronic ethanol feeding. Such changes may contribute to the postprandial hypertriacyglyceridemia observed in alcoholics.
Publisher: Wiley
Date: 23-11-2010
DOI: 10.1111/J.1440-1746.2010.06445.X
Abstract: Alcoholic pancreatitis is a major complication of alcohol abuse. The risk of developing pancreatitis increases with increasing doses of alcohol, suggesting that alcohol exerts dose-related toxic effects on the pancreas. However, it is also clear that only a minority of alcoholics develop the disease, indicating that an additional trigger may be required to initiate clinically evident pancreatic injury. It is now well established that alcohol is metabolized by the pancreas via both oxidative and non-oxidative metabolites. Alcohol and its metabolites produce changes in the acinar cells, which may promote premature intracellular digestive enzyme activation thereby predisposing the gland to autodigestive injury. Pancreatic stellate cells (PSCs) are activated directly by alcohol and its metabolites and also by cytokines and growth factors released during alcohol-induced pancreatic necroinflammation. Activated PSCs are the key cells responsible for producing the fibrosis of alcoholic chronic pancreatitis. Efforts to identify clinically relevant factors that may explain the susceptibility of some alcoholics to pancreatitis have been underway for several years. An unequivocal, functionally characterized, association is yet to be identified in clinical studies, although in the experimental setting, endotoxin has been shown to trigger overt pancreatic injury and to promote disease progression in alcohol-fed animals. Thus, while the molecular effects of alcohol on the pancreas have been increasingly clarified in recent years, identification of predisposing or triggering factors remains a challenge.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1053/J.GASTRO.2007.03.001
Abstract: Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually results in significant impairment of exocrine as well as endocrine functions of the gland. In Western societies, the commonest association of chronic pancreatitis is alcohol abuse. Our understanding of the pathogenesis of CP has improved in recent years, though important advances that have been made with respect to delineating the mechanisms responsible for the development of pancreatic fibrosis (a constant feature of CP) following repeated acute attacks of pancreatic necroinflammation (the necrosis-fibrosis concept). The pancreatic stellate cells (PSCs) are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis (such as ethanol, its metabolites or oxidant stress) or by cytokines released during pancreatic necroinflammation. In recent years, research effort has also focused on the genetic abnormalities that may predispose to CP. Genes regulating trypsinogen activation/inactivation and cystic fibrosis transmembrane conductance regulator (CFTR) function have received particular attention. Mutations in these genes are now increasingly recognized for their potential 'disease modifier' role in distinct forms of CP including alcoholic, tropical, and idiopathic pancreatitis. Treatment of uncomplicated CP is usually conservative with the major aim being to effectively alleviate pain, maldigestion and diabetes, and consequently, to improve the patient's quality of life. Surgical and endoscopic interventions are reserved for complications such as pseudocysts, abscess, and malignancy.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2016
Publisher: Frontiers Media SA
Date: 2012
Publisher: American Association for Cancer Research (AACR)
Date: 04-2008
DOI: 10.1158/0008-5472.CAN-07-2477
Abstract: Pancreatic stellate cells (PSC) produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fully elucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopic model of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed. In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSC secretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSC secretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with mice receiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumor size and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCs within tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence of pancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions induced the proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. The proliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence of neutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interaction between pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruit stromal cells to establish an environment that promotes cancer progression. [Cancer Res 2008 (7):2085–93]
Publisher: BMJ
Date: 08-1991
DOI: 10.1136/GUT.32.8.945
Abstract: Altered frequencies of alpha 1 antitrypsin phenotypes have been reported in patients with chronic pancreatitis, suggesting a possible genetic basis for in idual susceptibility to this disease. Alpha 1 antitrypsin phenotypes, with particular regard to alcoholic pancreatitis, were studied. Patients with alcoholic pancreatitis were compared with alcoholic control subjects with no history of pancreatic disease. Serum alpha 1 antitrypsin concentrations were raised in pancreatitis patients s led within one month of an acute attack of pancreatitis, but otherwise values were similar to those of control subjects. There were no significant differences in alpha 1 antitrypsin phenotypes between alcoholics with pancreatitis and alcoholic control subjects. This study of alpha 1 antitrypsin phenotypes provides no evidence of an inherited susceptibility to alcoholic pancreatitis.
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1053/J.GASTRO.2007.06.062
Abstract: This study examined the possible role of endotoxinemia (from increased gut permeability) as an additional trigger factor for overt pancreatic disease and as a promoter of chronic pancreatic injury in alcoholics by using a rat model of chronic alcohol feeding and in vitro experiments with cultured pancreatic stellate cells (PSCs), the key mediators of pancreatic fibrosis. In the in vivo model, Sprague-Dawley rats fed isocaloric Lieber-DeCarli liquid diets +/- alcohol for 10 weeks were challenged with a single dose or 3 repeated doses of the endotoxin lipopolysaccharide (LPS) and the pancreas was examined. In the in vitro studies, rat PSCs were assessed for activation on exposure to LPS +/- ethanol. The expression of LPS receptors TLR4 and CD14 also was assessed in rat and human PSCs. In the in vivo model, single or repeated LPS challenge resulted in significantly greater pancreatic injury in alcohol-fed rats compared with rats fed the control diet without alcohol. Notably, repeated LPS injections caused pancreatic fibrosis in alcohol-fed rats, but not in rats fed the control diet. In the in vitro studies, PSCs were activated by LPS. Alcohol + LPS exerted a synergistic effect on PSC activation. Importantly, both rat and human PSCs expressed TLR4 and CD14. This study describes, for the first time, a clinically relevant animal model of alcohol-related pancreatic injury and provides strong in vivo and in vitro evidence that suggests that LPS is a trigger factor in the initiation and progression of alcoholic pancreatitis.
Publisher: BMJ
Date: 10-2005
Publisher: Elsevier BV
Date: 06-1984
DOI: 10.1016/0006-291X(84)90216-X
Abstract: A technique for the isolation of functional rat pancreatic mitochondria is described. The resultant mitochondrial preparations contained oligomycin-insensitive Mg2+-ATPase activity and coupled respiration could only be demonstrated in the absence of Mg2+ and in the presence of EDTA.
Publisher: BMJ
Date: 2006
Publisher: BMJ
Date: 28-05-1994
Publisher: Routledge
Date: 15-02-2013
Publisher: Wiley
Date: 09-02-2012
DOI: 10.1111/J.1440-1746.2011.07000.X
Abstract: One of the characteristic features of the majority of pancreatic ductal adenocarcinomas is an abundant desmoplastic/stromal reaction. Until recently, this stroma had received little attention from researchers studying the pathogenesis of pancreatic cancer, with most of the research focus resting on the biology of tumor cells themselves. However, evidence is now accumulating that the stroma plays a critical role in pancreatic cancer progression. The cells responsible for producing the stromal reaction in pancreatic cancer are activated pancreatic stellate cells (PSCs, the key effector cells in pancreatic fibrogenesis). In vitro and in vivo studies have convincingly demonstrated a close bi-directional interaction between PSCs and pancreatic cancer cells, which facilitates local tumor growth as well as distant metastasis. PSCs also interact closely with endothelial cells to stimulate angiogenesis and are possibly involved in the known resistance of pancreatic cancer to chemotherapy and radiation. Most interestingly, it has recently been shown that PSCs from the primary tumor can travel to distant metastatic sites where they likely facilitate the seeding, survival, and proliferation of cancer cells. Thus, it is now recognized that the stroma is an important alternative therapeutic target in this disease and concerted pre-clinical research is underway to develop strategies to modulate/deplete the stromal reaction to inhibit cancer progression. The challenge is to translate these developments into clinically applicable treatments for patients.
Publisher: Wiley
Date: 09-1981
DOI: 10.1111/J.1530-0277.1981.TB05356.X
Abstract: The influence of ethanol on cardiac lipid metabolism has been investigated in the rat. Acute in vitro ethanol significantly stimulated the incorporation of 14C-1-acetate but not 14C-U-glucose into cardiac lipid in rats fed a diet free of ethanol for 3 weeks. Stimulation of incorporation was not uniform but was confined to the diglyceride and triglyceride fractions. This response of cardiac tissue lipid metabolism to acute ethanol was not observed in rats pair fed an isocaloric diet containing 36% of calories as ethanol. Chronic ethanol feeding significantly increased cardiac triglyceride content when compared with pair-fed controls. It also stimulated oxidation of labeled palmitate, but did not affect in vitro lipogenesis.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Wiley
Date: 12-1982
DOI: 10.1111/J.1530-0277.1982.TB05389.X
Abstract: To develop an animal mode of alcoholic pancreatic steatosis, female Wistar rats were pair fed liquid diets, containing ethanol as 36% of calories or an isocaloric amount of carbohydrate for 3 weeks. Electron microscopic examination showed lipid vesicles localized principally at the bases of pancreatic acinar cells in the ethanol-fed rats. Ethanol feeding significantly increased pancreatic content of cholesteryl ester without changing levels of other lipids. Ethanol feeding enhanced labeled acetate, palmitate, oleate, and linoleate incorporation into cholesteryl ester. Therefore, increased esterification of cholesterol may, in part, explain the observed accumulation of cholesteryl ester.
Publisher: Wiley
Date: 11-04-2008
Publisher: Springer Science and Business Media LLC
Date: 10-1988
DOI: 10.1007/BF01536675
Abstract: The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the 'C' subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so-called multidrug resistance proteins (MRPs) 1-9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C(4) and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this minireview, the current biochemical and physiological knowledge of MRP1-MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin-Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed.
Publisher: Frontiers Media SA
Date: 2014
Publisher: BMJ
Date: 02-2003
DOI: 10.1136/GUT.52.2.275
Abstract: Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury and is thought to result from a change in the balance between synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies suggest that activated pancreatic stellate cells (PSCs) play a central role in pancreatic fibrogenesis via increased synthesis of ECM proteins. However, the role of these cells in ECM protein degradation has not been fully elucidated. To determine: (i) whether PSCs secrete matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and, if so (ii) whether MMP and TIMP secretion by PSCs is altered in response to known PSC activating factors such as tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1), interleukin 6 (IL-6), ethanol, and acetaldehyde. Cultured rat PSCs (n=3-5 separate cell preparations) were incubated at 37 degrees C for 24 hours with serum free culture medium containing TNF-alpha (5-25 U/ml), TGF-beta1 (0.5-1 ng/ml), IL-6 (0.001-10 ng/ml), ethanol (10-50 mM), or acetaldehyde (150-200 micro M), or no additions (controls). Medium from control cells was examined for the presence of MMPs by zymography using a 10% polyacrylamide-0.1% gelatin gel. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine gene expression of MMP9 and the tissue inhibitors of metalloproteinases TIMP1 and TIMP2. Western blotting was used to identify a specific MMP, MMP2 (a gelatinase that digests basement membrane collagen and the dominant MMP observed on zymography) and a specific TIMP, TIMP2. Reverse zymography was used to examine functional TIMPs in PSC secretions. The effect of TNF-alpha, TGF-beta1, and IL-6 on MMP2 secretion was assessed by densitometry of western blots. The effect of ethanol and acetaldehyde on MMP2 and TIMP2 secretion was also assessed by this method. Zymography revealed that PSCs secrete a number of MMPs including proteinases with molecular weights consistent with MMP2, MMP9, and MMP13. RT-PCR demonstrated the presence of mRNA for metalloproteinase inhibitors TIMP1 and TIMP2 in PSCs while reverse zymography revealed the presence of functional TIMP2 in PSC secretions. MMP2 secretion by PSCs was significantly increased by TGF-beta1 and IL-6, but was not affected by TNF-alpha. Ethanol and acetaldehyde induced secretion of both MMP2 and TIMP2 by PSCs. Pancreatic stellate cells have the capacity to synthesise a number of matrix metalloproteinases, including MMP2, MMP9, and MMP13 and their inhibitors TIMP1 and TIMP2. MMP2 secretion by PSCs is significantly increased on exposure to the proinflammatory cytokines TGF-beta1 and IL-6. Both ethanol and its metabolite acetaldehyde increase MMP2 as well as TIMP2 secretion by PSCs. The role of pancreatic stellate cells in extracellular matrix formation and fibrogenesis may be related to their capacity to regulate the degradation as well as the synthesis of extracellular matrix proteins.
Publisher: S. Karger AG
Date: 2005
DOI: 10.1159/000090170
Abstract: Alcoholic pancreatitis is a major complication of alcohol abuse. Since only a minority of alcoholics develop pancreatitis, there has been a keen interest in identifying the factors that may confer in idual susceptibility to the disease. Numerous possibilities have been evaluated including diet, drinking patterns and a range of inherited factors. However, at the present time, no susceptibility factor has been unequivocally identified. In contrast, considerable progress has been made with respect to the constant effects of alcohol on the pancreas. The molecular mechanisms of alcohol-induced pancreatic injury are being increasingly defined with an emphasis, in recent years, on the acinar cell itself as the principal site on ethanol-related damage. It has now been established that the acinar cell is capable of metabolizing alcohol and that the direct toxic effects of alcohol and/or its metabolites on acinar cells may predispose the gland to autodigestive injury in the presence of an appropriate triggering factor. A significant recent development relates to the characterization of pancreatic stellate cells, increasingly implicated in alcoholic pancreatic fibrosis. Here the current concepts regarding the mechanisms athways mediating alcohol-induced pancreatic injury are outlined.
Publisher: Springer Science and Business Media LLC
Date: 05-1988
DOI: 10.1007/BF00212764
Abstract: Herpes simplex virus type 1 (HSV-1) is an important human pathogen and a leading cause of infectious blindness in the developed world. HSV-1 exploits heparan sulfate proteoglycans (HSPG) for attachment to cells. While the significance of heparan sulphate (HS) moieties in HSV-1 infection is well established, the role of specific proteoglycan core proteins in the infection process remains poorly understood. The objective of this study was to assess the roles of syndecan-1 and syndecan-2 core proteins in HSV-1 infection, both of which are expressed by many HSV-1 target cell types. Our results demonstrate that syndecan-1 and syndecan-2 gene silencing by RNA interference reduces HSV-1 entry, plaque formation and facilitates cell survival. Furthermore, HSV-1 infection increases syndecan-1 and syndecan-2 protein synthesis and a resultant increase in cell surface expression of HS. Our observations suggest that changes in syndecan-1 and syndecan-2 expression levels may be related to active viral infection. Taken together, our findings provide new insights into HSPG functions during HSV-1 entry and spread.
Publisher: Wiley
Date: 07-2008
DOI: 10.1111/J.1445-5994.2008.01715.X
Abstract: Chronic pancreatitis is a necroinflammatory process characterized pathologically by acinar atrophy and fibrosis and clinically by abdominal pain, diabetes and maldigestion. In this review we summarize some of the recent advances in the understanding of the pathogenesis of pancreatitis and how they have shaped our current understanding of chronic pancreatitis. We pay particular attention to advances in the genetic basis of idiopathic, hereditary and tropical pancreatitis as well as research into the relationship between alcohol and the pancreas. We have also reviewed current practices with respect to diagnosis and management of chronic pancreatitis.
Publisher: Georg Thieme Verlag KG
Date: 05-06-2013
Abstract: The aim of this study was to develop a new international classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric descriptions of occurrences that are merely associated with severity. A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensive medicine specialists, and radiologists who are currently active in clinical research on acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global Web-based survey was conducted and a dedicated international symposium was organised to bring contributors from different disciplines together and discuss the concept and definitions. The new international classification is based on the actual local and systemic determinants of severity, rather than descriptions of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity - mild, moderate, severe, and critical. This classification is the result of a consultative process amongst pancreatologists from 49 countries spanning North America, South America, Europe, Asia, Oceania, and Africa. It provides a set of concise up-to-date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2004
DOI: 10.1097/00006676-200410000-00002
Abstract: Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor. Serial sections of human pancreatic cancer tissue were stained for desmin and glial fibrillary acidic protein (stellate cell selective markers) and alpha-smooth muscle actin (alphaSMA), a marker of activated PSC activation, by immunohistochemistry, and for collagen using Sirius Red. Correlation between the extent of positive staining for collagen and alphaSMA was assessed by morphometry. The cellular source of collagen in stromal areas was identified using dual staining methodology, ie, immunostaining for alphaSMA and in situ hybridization for procollagen alpha1I mRNA. The possible interaction between pancreatic cancer cells and PSCs was assessed in vitro by exposing cultured rat PSCs to control medium or conditioned medium from 2 pancreatic cancer cell lines (PANC-1 and MiaPaCa-2) for 24 hours. PSC activation was assessed by cell proliferation and alphaSMA expression. Stromal areas of human pancreatic cancer stained strongly positive for the stellate cell selective markers desmin and GFAP (indicating the presence of PSCs), for alphaSMA (suggesting that the PSCs were in their activated state) and for collagen. Morphometric analysis demonstrated a close correlation (r = 0.77 P < 0.04 8 paired sections) between the extent of PSC activation and collagen deposition. Procollagen mRNA expression was localized to alphaSMA-positive cells in stromal areas indicating that activated PSCs were the predominant source of collagen in stromal areas. Exposure of PSCs to pancreatic cancer cell secretions in vitro resulted in PSC activation as indicated by significantly increased cell proliferation and alphaSMA expression. Activated PSCs are present in the stromal reaction in pancreatic cancers and are responsible for the production of stromal collagen. PSC function is influenced by pancreatic cancer cells. Interactions between tumor cells and stromal cells (PSCs) may play an important role in the pathobiology of pancreatic cancer.
Publisher: Elsevier BV
Date: 1996
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.MEDIN.2013.03.013
Abstract: To develop a new classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of the published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of specialist in pancreatic diseases, but are suboptimal because these definitions are based on the empiric description of events not associated with severity. A personal invitation to contribute to the development of a new classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists and radiologists currently active in the field of clinical acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global web-based survey was conducted, and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. The new classification of severity is based on the actual local and systemic determinants of severity, rather than on the description of events that are non-causally associated with severity. The local determinant relates to whether there is (peri) pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another, whereby the presence of both infected (peri) pancreatic necrosis and persistent organ failure has a greater impact upon severity than either determinant alone. The derivation of a classification based on the above principles results in four categories of severity: mild, moderate, severe, and critical. This classification is the result of a consultative process among specialists in pancreatic diseases from 49 countries spanning North America, South America, Europe, Asia, Oceania and Africa. It provides a set of concise up to date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.PAN.2015.12.006
Abstract: Because of increasing awareness of variations in the use of pancreatic exocrine replacement therapy, the Australasian Pancreatic Club decided it was timely to re-review the literature and create new Australasian guidelines for the management of pancreatic exocrine insufficiency (PEI). A working party of expert clinicians was convened and initially determined that by iding the types of presentation into three categories for the likelihood of PEI (definite, possible and unlikely) they were able to consider the difficulties of diagnosing PEI and relate these to the value of treatment for each diagnostic category. Recent studies confirm that patients with chronic pancreatitis receive similar benefit from pancreatic exocrine replacement therapy (PERT) to that established in children with cystic fibrosis. Severe acute pancreatitis is frequently followed by PEI and PERT should be considered for these patients because of their nutritional requirements. Evidence is also becoming stronger for the benefits of PERT in patients with unresectable pancreatic cancer. However there is as yet no clear guide to help identify those patients in the 'unlikely' PEI group who would benefit from PERT. For ex le, patients with coeliac disease, diabetes mellitus, irritable bowel syndrome and weight loss in the elderly may occasionally be given a trial of PERT, but determining its effectiveness will be difficult. The starting dose of PERT should be from 25,000-40,000 IU lipase taken with food. This may need to be titrated up and there may be a need for proton pump inhibitors in some patients to improve efficacy.
Publisher: Wiley
Date: 18-08-2008
DOI: 10.1111/J.1440-1746.2008.05520.X
Abstract: Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.
Publisher: Wiley
Date: 14-10-2015
DOI: 10.1111/ACER.12882
Abstract: Chronic pancreatitis, a known complication of alcohol abuse, is characterized histopathologically by prominent fibrosis. Pancreatic stellate cells (PSCs) are responsible for producing this fibrous tissue in chronic pancreatitis and are activated by alcohol. Progression of alcoholic chronic pancreatitis (as assessed by calcification and fibrosis) is thought to be facilitated by concurrent smoking, but the mechanisms are unknown. This study aimed to (a) determine whether human PSCs (hPSCs) and rat PSCs express nicotinic acetylcholine receptors (nAChRs), which are known to bind 2 important components of cigarette smoke, namely nicotine and nicotine-derived nitrosamine ketone (NNK), and (b) examine the effects of cigarette smoke components in the presence and absence of alcohol on PSC activation in vitro. Western blotting was used to detect the presence of nAChRs in primary cultures of PSCs. Clinically relevant concentrations of cigarette smoke components (either cigarette smoke extract [CSE], NNK, or nicotine) ± ethanol (EtOH) were used to treat primary cultures of PSCs, and stellate cell activation was assessed by cell migration, proliferation, collagen production, and apoptosis. We demonstrate, for the first time, that PSCs express nAChRs (isoforms α3, α7, β, ε) and that the expression of the α7 isoform in hPSCs is induced by CSE + EtOH. We also provide novel findings that PSCs are activated by CSE and NNK (both alone and in combination with EtOH) as evidenced by an increase in cell migration and/or proliferation. Further, we demonstrate that activation of PSCs by CSE + EtOH and NNK + EtOH may be mediated via nAChRs on the cells. PSCs are activated by clinically relevant concentrations of cigarette smoke components (CSE and NNK), alone and in combination with EtOH. Thus, in alcoholics who smoke, progression of pancreatic fibrosis may be facilitated by the combined effects of alcohol and cigarette smoke components on hPSC behavior.
Publisher: BMJ
Date: 04-2002
DOI: 10.1136/GUT.50.4.535
Abstract: It is now generally accepted that chronic pancreatic injury and fibrosis may result from repeated episodes of acute pancreatic necroinflammation (the necrosis-fibrosis sequence). Recent studies suggest that pancreatic stellate cells (PSCs), when activated, may play an important role in the development of pancreatic fibrosis. Factors that may influence PSC activation during pancreatic necroinflammation include cytokines known to be important in the pathogenesis of acute pancreatitis, such as tumour necrosis factor alpha (TNF-alpha), and the interleukins 1, 6, and 10 (IL-1, IL-6, and IL-10). To determine the effects of these cytokines on PSC activation, as assessed by cell proliferation, alpha smooth muscle actin (alpha-SMA) expression, and collagen synthesis. Cultured rat PSCs were incubated with cytokines for 24 hours. Cell proliferation was assessed by measuring (3)H thymidine incorporation into cellular DNA, alpha-SMA expression by western blotting, and collagen synthesis by incorporation of (14)C proline into collagenase sensitive protein. mRNA levels for procollagen alpha(1)(1) in PSCs were determined by northern and dot blotting methods. Expression of alpha-SMA by PSCs was increased on exposure to each of the cytokines used in the study. Stellate cell proliferation was stimulated by TNF-alpha but inhibited by IL-6, while IL-1 and IL-10 had no effect on PSC proliferation. Collagen synthesis by PSCs was stimulated by TNF-alpha and IL-10, inhibited in response to IL-6, and unaltered by IL-1. Changes in collagen protein synthesis in response to TNF-alpha, IL-10, and IL-6 were not regulated at the mRNA level in the cells. This study has demonstrated that PSCs have the capacity to respond to cytokines known to be upregulated during acute pancreatitis. Persistent activation of PSCs by cytokines during acute pancreatitis may be a factor involved in the progression from acute pancreatitis to chronic pancreatic injury and fibrosis.
Publisher: Elsevier BV
Date: 2004
DOI: 10.1159/000077608
Publisher: Elsevier BV
Date: 12-1984
DOI: 10.1016/0014-4800(84)90016-9
Abstract: In a previous study, a rat model of ethanol-induced pancreatic steatosis was developed in which chronic ethanol feeding resulted in a twofold increase in pancreatic cholesteryl ester content. The studies reported here were performed in order to elucidate the mechanism of this cholesteryl ester accumulation. Rats were pair fed ethanol or control diets for 3 weeks. Ethanol feeding resulted in an increased accumulation of serum cholesterol in the pancreas. Ethanol feeding also resulted in increased in vitro incorporation of labeled acetate and mevalonate into the sterol moiety of pancreatic cholesteryl ester and increased incorporation of labeled acetate into its fatty acid component. These results suggest that chronic ethanol feeding causes pancreatic cholesteryl ester accumulation by affecting exchange of cholesterol between serum and pancreatic tissue.
Publisher: Elsevier BV
Date: 09-1983
DOI: 10.1016/S0006-291X(83)80001-1
Abstract: Stimulation of the exocrine pancreas is associated with marked changes in pancreatic phospholipid metabolism. It has been previously established that de novo synthesis of phospholipids constitutes part of this "phospholipid effect". This study has demonstrated that in vitro stimulation of the rat pancreas utilising bethanecol and pancreozymin results in increased incorporation of labelled glucose into phosphatidyl inositol and, to a lesser extent, other phospholipids, suggesting increased de novo synthesis of these compounds. However, secretin which is believed to act via a different intracellular pathway, did not exert such an effect. The relevance of this animal model is indicated by the demonstration of increased incorporation of labelled glucose into phospholipids of human pancreas stimulated in vitro by bethanecol or sincalide (the active carboxy terminal octapeptide of pancreozymin).
Publisher: Springer Science and Business Media LLC
Date: 06-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1999
Publisher: Oxford University Press (OUP)
Date: 29-05-2014
Abstract: Activated cancer-associated human pancreatic stellate cells (CAhPSCs, which produce the collagenous stroma of pancreatic cancer [PC]) are known to play a major role in PC progression. Apart from inducing cancer cell proliferation and migration, CAhPSCs have also been implicated in neoangiogenesis in PC. However, the mechanisms mediating the observed angiogenic effects of CAhPSCs are unknown. A candidate pathway that may be involved in this process is the hepatocyte growth factor (HGF)/c-MET pathway and its helper molecule, urokinase-type plasminogen activator (uPA). This study investigated the effects of CAhPSC secretions on endothelial cell function in the presence and absence of HGF, c-MET and uPA inhibitors. HGF levels in CAhPSC secretions were quantified using ELISA. CAhPSC secretions were then incubated with human microvascular endothelial cells (HMEC-1) and angiogenesis assessed by quantifying HMEC-1 tube formation and proliferation. CAhPSC-secreted HGF significantly increased HMEC-1 tube formation and proliferation notably, these effects were downregulated by inhibition of HGF, its receptor c-MET and uPA. Phosphorylation of p38 mitogen-activated protein kinase was downregulated during inhibition of the HGF/c-MET pathway, whereas phosphatidylinositol-3 kinase and ERK1/2 remained unaffected. Our studies have shown for the first time that CAhPSCs induce proliferation and tube formation of HMEC-1 and that the HGF/c-MET pathway plays a major role in this induction. Given that standard antiangiogenic treatment targeting vascular endothelial growth factor has had limited success in the clinical setting, the findings of the current study provide strong support for a novel, alternative antiangiogenic approach targeting the HGF/c-MET and uPA pathways in PC.
Publisher: Elsevier BV
Date: 07-1997
Publisher: Informa UK Limited
Date: 10-02-2014
DOI: 10.1586/14737159.2014.883277
Abstract: The diagnostic options for chronic pancreatitis have evolved over recent years. The previous gold standard references for structural imaging and exocrine pancreatic function testing have both been supplanted and redesigned. Endoscopic retrograde pancreatography has now been overtaken by endoscopic ultrasound and magnetic resonance cholangiopancreatography, whilst the old technique for Dreiling tube pancreatic function testing has now been replaced by the endoscopic pancreatic function test. New advances in endoscopic ultrasound elastography have also extended the options for evaluating pancreatic masses to differentiate mass-forming chronic pancreatitis from malignancy. Genetic contribution to chronic pancreatitis is also now more widely recognized than ever before.
Publisher: S. Karger AG
Date: 2004
DOI: 10.1159/000082799
Abstract: Pancreatic fibrosis, a characteristic histopathological feature of chronic pancreatitis, is no longer considered an epiphenomenon of chronic injury, but an active process that may be reversible in the early stages. The identification and characterization of pancreatic stellate cells (PSCs) in recent years has had a significant impact on research into pancreatic fibrogenesis. Accumulating evidence from both in vivo studies (using human pancreatic sections and experimental models of pancreatic fibrosis) and in vitro studies (using cultured pancreatic stellate cells) indicates a key role for activated PSCs in the fibrotic process. These cells are now known to be activated by ethanol and its metabolites and by several factors that are upregulated during pancreatic injury including growth factors, cytokines and oxidant stress. Based on this knowledge, potential antifibrotic strategies such as antioxidants and cytokine inhibition have been assessed in experimental models. Studies are also underway to characterise the signaling pathways/molecules responsible for mediating PSC activation, in order to identify potential therapeutic targets for the inhibition of PSC activation, thereby preventing or reversing the development of pancreatic fibrosis.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2015
Publisher: Elsevier BV
Date: 11-2010
Publisher: Elsevier BV
Date: 2000
DOI: 10.1016/S0024-3205(99)00630-X
Abstract: The interactions between alcohol and cytochrome P-450 enzymes have been well investigated. However, the data regarding the effect of alcohol on the regulation of UDP-glucuronosyltranferase (UGT) activity are less clear. The aim of the present study was to determine the role of alcohol in the regulation of UGT mRNA expression by using whole animal and primary cultured hepatocytes. Chronic ethanol feeding of rats significantly increased the expression of liver UGT1A1 mRNA to 177% of control. The mRNA levels for UGT1A5, UGT2B1 and UGT2B3 were also enhanced, but did not reach statistical significance. In cultured hepatocytes, treatment with either ethanol or isopentanol significantly increased the expression of UGT1A1, UGT1A5, UGT2B1, and UGT2B3 mRNAs, but to different degrees. The induction of UGT1A1 and UGT2B1 mRNAs by ethanol or isopentanol was time-dependent and maximal changes occurred at 48 h. The expression of UGT1A6 mRNA was not significantly modified by either ethanol or isopentanol. In conclusion, ethanol and isopentanol have direct roles in the regulation of UGT.
Publisher: Wiley
Date: 22-08-2006
DOI: 10.1111/J.1440-1746.2006.04587.X
Abstract: Pancreatic stellate cells (PSC) are now recognized as the key mediators of pancreatic fibrosis, a characteristic feature of chronic pancreatitis. The role of PSC in alcoholic pancreatic fibrosis has been examined in vivo (using pancreatic tissue from patients with alcohol-induced chronic pancreatitis and from animal models of experimental pancreatitis) and in vitro (using PSC in culture). These studies indicate that PSC are activated early in the course of pancreatic injury and are the predominant source of collagen in the fibrotic pancreas. The factors responsible for mediating PSC activation during chronic alcohol exposure include ethanol, its metabolite acetaldehyde, oxidant stress and cytokines (released during episodes of alcohol-induced pancreatic necroinflammation). Most recently, the intracellular signaling mechanisms regulating ethanol-induced PSC activation have been identified and include the mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), and the transcription factor activator protein-1 (AP-1).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2003
DOI: 10.1097/00006676-200308000-00008
Abstract: Pancreatic fibrosis is a characteristic feature of alcoholic chronic pancreatitis. Recent studies suggest that activated pancreatic stellate cells (PSCs) are the major cell-type involved in pancreatic fibrogenesis. Cultured PSCs become activated when exposed to ethanol or its metabolite acetaldehyde (as indicated by increased alpha-smooth muscle actin [alpha-SMA] expression and increased collagen synthesis). However the intracellular signaling mechanisms responsible for ethanol- or acetaldehyde-induced PSC activation remain to be fully elucidated. One of the major signaling pathways known to regulate protein synthesis in mammalian cells is the mitogen-activated protein kinase (MARK) pathway. To examine the effects of ethanol and acetaldehyde on the MAPK pathway (by assessing the activities of the 3 major subfamilies (extracellular-regulated kinases 1 and 2 [ERK 1/2], JNK and p38 kinase) in PSCs and to examine the role of p38 kinase in mediating the ethanol- and acetaldehyde-induced increase in alpha-SMA expression in activated rat PSCs. Rat PSCs were incubated with ethanol (50 mM) or acetaldehyde (200 microM) for 15 min, 30 min, 60 min, and 24 h and activities of ERK 1/2, JNK, and p38 kinase were assessed in cell lysates using kinase assays and Western blot. In addition, rat PSCs were treated with the specific p38 MAPK inhibitor SB203580 in the presence or absence of ethanol or acetaldehyde for 24h, and activation of the downstream protein kinase MAPKAP kinase-2 (an indicator of p38 MAPK activity) was assessed by Western blot. Specific inhibitors were also used to inhibit the activity of ERK 1/2 and JNK. Following inhibition of the above signaling pathways, alpha-SMA expression by PSCs was assessed by Western blot. Ethanol and acetaldehyde increased the activation of all 3 subfamilies (ERK 1/2, JNK and p38 kinase) of the MAPK pathway in PSCs. Treatment of PSCs with SB203580 abolished the ethanol- and acetaldehyde-induced increase in p38 MAPK activity and also prevented the induction of alpha-SMA expression in PSCs. However, inhibition of ERK 1/2 and JNK had no effect on ethanoland acetaldehyde-induced alpha-SMA expression in PSCs. (1) The MAP kinase pathway is induced in PSCs after exposure to ethanol or acetaldehyde and this induction is sustained for at least 24h. (2) The p38 MAPK pathway mediates the activation (as indicated by increased alpha-SMA expression) of PSCs by ethanol or acetaldehyde.
Publisher: Elsevier BV
Date: 05-2013
Publisher: Elsevier BV
Date: 07-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2003
DOI: 10.1097/00006676-200311000-00008
Abstract: The pathogenesis of pancreatic fibrosis, a characteristic feature of alcohol-induced chronic pancreatitis, has received increasing attention over the past few years, largely due to the identification and characterization of stellate cells in the pancreas. These cells are morphologically similar to hepatic stellate cells, the principal effector cells in liver fibrosis. The role of pancreatic stellate cells (PSCs) in alcoholic pancreatic fibrosis has been studied using 2 approaches: (i) in vivo studies using pancreatic tissue from patients with alcohol-induced chronic pancreatitis and from animal models of experimental pancreatitis and (ii) in vitro studies using cultured PSCs. These studies indicate that PSCs are activated early in the course of pancreatic injury and are the predominant source of collagen in the fibrotic pancreas. Several factors that may be responsible for mediating PSC activation during chronic alcohol exposure have also been identified. From the findings to date, it may be speculated that the pathogenesis of alcoholic pancreatic fibrosis may involve 2 pathways: (i) a necroinflammatory pathway involving cytokine release and PSC activation and (ii) a nonnecroinflammatory pathway involving direct activation of PSCs by ethanol via its metabolism to acetaldehyde and the generation of oxidant stress.
Publisher: American Physiological Society
Date: 15-09-2013
Abstract: Activated pancreatic stellate cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs cultured on plastic, a nonphysiological surface. However, PSCs cultured on physiological matrices, e.g., Matrigel (normal basement membrane) and collagen (fibrotic pancreas), may have distinctly different behaviors compared with cells cultured on plastic. Therefore, we aimed to 1) compare PSC gene expression after culture on plastic, Matrigel, and collagen I 2) validate the gene array data for transgelin, the most highly dysregulated gene in PSCs grown on activating vs. nonactivating matrices, at mRNA and protein levels 3) examine the role of transgelin in PSC function and 4) assess transgelin expression in human chronic pancreatitis sections. Culture of PSCs on different matrices significantly affected their gene expression pattern. 146, 619, and 432 genes, respectively, were differentially expressed ( P 0.001) in PSCs cultured on collagen I vs. Matrigel, Matrigel vs. plastic, and collagen I vs. plastic. The highest fold change (12.5-fold upregulation) in gene expression in cells on collagen I vs. Matrigel was observed for transgelin (an actin stress fiber-associated protein). Transgelin was significantly increased in activated PSCs vs. quiescent PSCs. Silencing transgelin expression decreased PSC proliferation and also reduced platelet-derived growth factor-induced PSC migration. Notably, transgelin was highly expressed in chronic pancreatitis in stromal areas and periacinar spaces but was absent in acinar cells. These findings suggest that transgelin is a potentially useful target protein to modulate PSC function so as to ameliorate pancreatic fibrosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2003
DOI: 10.1097/00006676-200311000-00007
Abstract: Metabolism of ethanol by acinar and other pancreatic cells and the consequent generation of toxic metabolites are postulated to play an important role in the development of alcohol-related acute and chronic pancreatic injury. Studies using cultured pancreatic acinar cells and isolated pancreatic acini have established that (i) the pancreas can metabolize ethanol via the oxidative pathway involving the enzymes alcohol dehydrogenase (ADH) and possibly cytochrome P4502E1 (although the role of the latter remains to be fully delineated) as well as the nonoxidative pathway [involving fatty acid ethyl ester (FAEE) synthases] and (ii) the oxidative pathway (which generates acetaldehyde) is quantitatively greater than the nonoxidative pathway, which yields FAEEs. Most recently, pancreatic stellate cells (PSCs) (implicated in pancreatic fibrogenesis) have been reported to exhibit ADH activity, suggesting that the capacity of the pancreas to metabolize ethanol may reside not only in parenchymal (acinar) cells but also in nonparenchymal cells. Polymorphisms/mutations of ethanol metabolizing enzymes have been examined to determine whether they may confer in idual susceptibility to alcoholic pancreatitis. However, no association has been demonstrated between ADH and CYP2E1 polymorphisms and the predisposition to alcoholic pancreatitis. Other candidate factors that remain to be studied include polymorphisms of FAEE synthetic enzymes and proteins relevant to antioxidant pathways in the cell. Injury to the pancreas due to its capacity to metabolize ethanol may be mediated by direct effects of both acetaldehyde and FAEEs and by alterations induced within the cells during ethanol metabolism, such as changes in the intracellular redox state and the generation of oxidant stress.
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S1521-6918(03)00050-7
Abstract: Alcoholic pancreatitis is a major complication of alcohol abuse. Until recently, it was generally accepted that alcoholic pancreatitis was a chronic disease from the outset. However, evidence is now emerging in support of the 'necrosis-fibrosis' hypothesis that alcoholic pancreatitis begins as an acute process and that repeated episodes of acute injury lead to the changes of chronic pancreatitis (acinar atrophy and fibrosis) resulting in exocrine and endocrine dysfunction. The treatment of acute pancreatitis follows the regimen of bed rest, nasogastric suction, analgesia and intravenous support. The role of additional therapeutic measures such as prophylactic antibiotics, antioxidants and enteral nutrition in severe cases has not yet been precisely defined. The treatment of chronic pancreatitis involves attention to its three cardinal features: pain, maldigestion and diabetes. With respect to the pathogenesis of alcoholic pancreatitis, the focus of research over the past 30 years has shifted from the sphincter of Oddi and ductular abnormalities to the acinar cell itself. It has now been established that the acinar cell is capable of metabolizing alcohol and that direct toxic effects of alcohol and/or its metabolites on acinar cells may predispose the gland to injury in the presence of an appropriate trigger factor. A significant recent development relates to the characterization of pancreatic stellate cells, increasingly implicated in alcoholic pancreatic fibrosis. This chapter summarizes the natural history, clinical features, current trends in treatment as well as recent advances in our understanding of the pathogenesis of alcoholic pancreatitis.
Publisher: Elsevier BV
Date: 03-1998
Publisher: BMJ
Date: 05-2003
DOI: 10.1136/GUT.52.5.677
Abstract: Pancreatic stellate cells (PSCs), implicated as key mediators of pancreatic fibrogenesis, are found in increased numbers in areas of pancreatic injury. This increase in PSC number may be due to increased local proliferation and/or migration of these cells from adjacent areas. The ability of PSCs to proliferate has been well established but their potential for migration has not been examined. Therefore, the aims of this study were to determine whether cultured rat PSCs have the capacity to migrate and, if so, to characterise this migratory capacity with respect to the influence of basement membrane components and the effect of platelet derived growth factor (PDGF, a known stimulant for migration of other cell types). Migration of freshly isolated (quiescent) and culture activated (passaged) rat PSCs was assessed across uncoated or Matrigel (a basement membrane-like substance) coated porous membranes (pore size 8 micro m) in the presence or absence of PDGF (10 and 20 ng/ml) in the culture medium. A checkerboard assay was performed to assess whether the effect of PDGF on PSC migration was chemotactic or chemokinetic. Cell migration was observed with both freshly isolated and passaged PSCs. However, compared with passaged (culture activated) cells, migration of freshly isolated cells was delayed, occurring only at or after 48 hours of incubation when the cells displayed an activated phenotype. PSC migration through Matrigel coated membranes was delayed but not prevented by basement membrane components. PSC migration was increased by PDGF and this effect was predominantly chemotactic (that is, in the direction of a positive concentration gradient). (i) PSCs have the capacity to migrate. (ii) Activation of PSCs appears to be a prerequisite for migration. (iii) PDGF stimulates PSC migration and this effect is predominantly chemotactic. Chemotactic factors released during pancreatic injury may stimulate the migration of PSCs through surrounding basement membrane towards affected areas of the gland.
Publisher: American Association for Cancer Research (AACR)
Date: 30-09-2008
DOI: 10.1158/0008-5472.CAN-08-1132
Abstract: Pancreatic cancer—a tumor displaying a particularly abundant stromal reaction—is notorious for its poor prognosis. Recent studies, via newly developed orthotopic models, provide compelling evidence of an important role for pancreatic stellate cells (PSC) in pancreatic cancer progression. Characterization of the mechanisms mediating PSC-cancer interactions will lead to the development of much needed alternative therapeutic approaches to improve disease outcome. [Cancer Res 2008 (19):7707–10]
Publisher: Baishideng Publishing Group Inc.
Date: 2014
Publisher: BMJ
Date: 09-1985
DOI: 10.1136/GUT.26.9.882
Abstract: To determine whether increased intakes of fat and protein or particular drinking habits are associated with the development of alcoholic pancreatitis, a dietary study has been conducted. Patients with clinically evident alcoholic pancreatitis were compared with in iduals with clinically evident alcoholic cirrhosis with respect to dietary and drinking habits before the onset of clinical illness. There was no significant difference between the two groups regarding intake of nutrients, drinking habits or type of alcoholic beverage consumed.
Publisher: Mary Ann Liebert Inc
Date: 15-11-2011
Abstract: Prominent fibrosis is a major histological feature of chronic pancreatitis, a progressive necroinflammatory condition of the pancreas, most commonly associated with alcohol abuse. Patients with this disease often develop exocrine and endocrine insufficiency characterized by maldigestion and diabetes. Up until just over a decade ago, there was little understanding of the pathogenesis of pancreatic fibrosis in chronic pancreatitis. In recent times, significant progress has been made in this area, mostly due to the identification, isolation, and characterization of the cells, namely pancreatic stellate cells (PSCs) that are now established as key players in pancreatic fibrogenesis. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. During pancreatic injury, PSCs transform into an activated phenotype that secretes excessive amounts of the ECM proteins that comprise fibrous tissue. This Review summarizes current knowledge and critical aspects of PSC biology which have been increasingly well characterized over the past few years, particularly with respect to the response of PSCs to factors that stimulate or inhibit their activation and the intracellular signaling pathways governing these processes. Based on this knowledge, several therapeutic strategies have been examined in experimental models of pancreatic fibrosis, demonstrating that pancreatic fibrosis is a potentially reversible condition, at least in early stages. These will involve translation of the laboratory findings into effective clinical approaches to prevent/inhibit PSC activation so as to prevent, retard, or reverse the fibrotic process in pancreatitis.
Publisher: Elsevier BV
Date: 07-2014
Publisher: Proceedings of the National Academy of Sciences
Date: 17-09-2010
Abstract: The pancreatic secretagogue cholecystokinin (CCK) is widely thought to stimulate enzyme secretion by acinar cells indirectly via activation of the vagus nerve. We postulate an alternative pathway for CCK-induced pancreatic secretion. We hypothesize that neurally related pancreatic stellate cells (PSCs located in close proximity to the basolateral aspect of acinar cells) play a regulatory role in pancreatic secretion by serving as an intermediate target for CCK and secreting the neurotransmitter acetylcholine (ACh), which, in turn, stimulates acinar enzyme secretion. To determine whether PSCs ( i ) exhibit CCK-dependent ACh secretion and ( ii ) influence acinar enzyme secretion, primary cultures of human and rat PSCs were used. Immunoblotting and/or immunofluorescence was used to detect choline acetyltransferase (ACh synthesizing enzyme), vesicular ACh transporter (VAChT), synaptophysin, and CCK receptors 1 and 2. Synaptic-like vesicles in PSCs were identified by EM. ACh secretion by PSCs exposed to 20 pM CCK was measured by LC-MS/MS. Amylase secretion by acini [pretreated with and without the muscarinic receptor antagonist atropine (10 μM) and cocultured with PSCs] was measured by colorimetry. PSCs express ACh synthesizing enzyme, VAChT, synaptophysin, and CCK receptors exhibit CCK-dependent ACh secretion and stimulate amylase secretion by acini, which is blocked by atropine. In conclusion, PSCs express the essential elements for ACh synthesis and secretion. CCK stimulates ACh secretion by PSCs, which, in turn, induces amylase secretion by acini. Therefore, PSCs may represent a previously unrecognized intrapancreatic pathway regulating CCK-induced pancreatic exocrine secretion.
Publisher: Wiley
Date: 02-2002
DOI: 10.1046/J.1440-1746.2002.02670.X
Abstract: Susceptibility to organ damage induced by alcohol may be due to inherited variation (polymorphism) in ethanol-metabolizing enzymes, or to polymorphisms affecting free radical or lipid metabolism mediated by enzymes such as glutathione S-transferases and apolipoprotein E. The aim was to compare the genotype frequencies of alcohol dehydrogenase-2 (ADH2), ADH3, aldehyde dehydrogenase-2 (ALDH2), cytochrome P450-2E1 (CYP2E1), glutathione S-transferase-M1 (GSTM1), GSTT1, and apolipoprotein E in patients with alcoholic cirrhosis and alcoholic chronic pancreatitis to those in control groups. The case-control study was restricted to Caucasian adults: 57 with alcoholic cirrhosis, 71 with alcoholic chronic pancreatitis, 57 alcoholics without apparent organ damage and 200 healthy blood donors. Genotypes were determined by restriction fragment length polymorphism after lification of genomic DNA by polymerase chain reaction. The genotype ADH3*2/*2 was more frequent in patients with cirrhosis (40%) than blood donors (12% OR 4.92, 95% CI 2.36-10.31) and patients with chronic pancreatitis (8% OR 7.33, 95% CI 2.54-23.78) but was not significantly different from alcoholic controls (23% OR 2.27, 95% CI 0.95-5.66). Patients with cirrhosis also had a higher frequency (P < 0.05) of ADH2*1/*1 (100%) than blood donors (92%) and those with chronic pancreatitis (93%). The frequencies of genotypes of ALDH2, CYP2E1, GSTM1, GSTT1 and apolipoprotein E were similar in all groups. Alcoholic cirrhosis but not alcoholic chronic pancreatitis is associated with ADH3*2/*2 and perhaps with ADH2*1/*1. Both genes encode less active alcohol-metabolizing enzymes that may be associated with cirrhosis because of delayed formation of acetaldehyde (with higher intakes of alcohol), or ersion of alcohol metabolism through pathways other than ADH.
Publisher: Springer Science and Business Media LLC
Date: 08-1984
DOI: 10.1007/BF01312945
Abstract: More than 2500 nuclear encoded preproteins are required for the function of chloroplasts in terrestrial plants. These preproteins are imported into chloroplasts via the concerted action of two multi-subunit translocons of the outer (TOC) and inner (TIC) membranes of the chloroplast envelope. This general import machinery functions to recognize and import proteins with high fidelity and efficiency to ensure that organelle biogenesis is properly coordinated with developmental and physiological events. Two components of the TOC machinery, Toc34 and Toc159, act as the primary receptors for preproteins at the chloroplast surface. They interact with the intrinsic targeting signals (transit peptides) of preproteins to mediate the selectivity of targeting, and they contribute to the quality control of import by constituting a GTP-dependent checkpoint in the import reaction. The TOC receptor family has expanded to regulate the import of distinct classes of preproteins that are required for remodeling of organelle proteomes during plastid-type transitions that accompany developmental changes. As such, the TOC receptors function as central regulators of the fidelity, specificity and selectivity of the general import machinery, thereby contributing to the integration of protein import with plastid biogenesis.
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0016-5085(99)70389-6
Abstract: A valid technique for the detection of esophagopharyngeal acid regurgitation would be valuable to evaluate suspected reflux-related otolaryngologic and respiratory disorders. The aim of this study was to derive pH criteria that optimally define esophagopharyngeal acid regurgitation and to examine patterns of regurgitation. In 19 healthy controls and 15 patients with suspected regurgitation, dual or quadruple pH sensors were used to monitor pharyngeal and esophageal pH. For each combination of the 2 variables, DeltapH and nadir pH, proportions of pH decreases that occurred during or independent of esophageal acidification were calculated to determine the likelihood that an in idual pharyngeal pH decrease was a candidate regurgitation event or a definite artifact. Overall, 92% of pharyngeal pH decreases of 1-2 pH units and 66% of pH decreases of this magnitude reaching a nadir pH of 2 units, and reached a nadir of <4 units in less than 30 seconds. Regurgitation occurred more frequently in subjects in an upright (32 of 35) than in a supine (3 of 35 events P </= 0.0001) position and was more frequently abrupt (synchronous with esophageal acidification) than delayed (P </= 0.05). Accepted criteria for gastroesophageal reflux are not applicable to the detection of esophagopharyngeal acid regurgitation, and most regurgitation occurs abruptly and in upright position.
Publisher: Elsevier BV
Date: 03-2006
Publisher: BMJ
Date: 24-09-2010
Abstract: Administration of repeated lipopolysaccharide (LPS) injections in alcohol-fed rats leads to significant pancreatic injury including fibrosis. However, it remains unknown whether alcoholic (chronic) pancreatitis has the potential to regress when alcohol is withdrawn. The aims of the study were (1) to compare the effect of alcohol withdrawal/continuation on pancreatic acute injury and fibrosis and (2) to assess the effects of alcohol ± LPS on pancreatic stellate cell (PSC) apoptosis in vivo and in vitro. Rats fed isocaloric Liebere-De-Carli liquid diets ± alcohol for 10 weeks were challenged with LPS (3 mg/kg/week for 3 weeks) and then either switched to control diet or maintained on an alcohol diet for 3 days, 7 days or 3 weeks. Pancreatic sections were assessed for acute tissue injury, fibrosis, PSC apoptosis and activation. Cultured rat PSCs were exposed to 10 mM ethanol 6 1 mg/ml LPS for 48 or 72 h and apoptosis was assessed (Annexin V, caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)). Withdrawal of alcohol led to resolution of pancreatic lesions including fibrosis and to increased PSC apoptosis. Continued alcohol administration perpetuated pancreatic injury and prevented PSC apoptosis. Alcohol and LPS significantly inhibited PSC apoptosis in vitro, and the effect of LPS on PSC apoptosis could be blocked by Toll-like receptor 4 small interfering RNA. Induction of PSC apoptosis upon alcohol withdrawal is a key mechanism mediating the resolution of pancreatic fibrosis. Conversely, continued alcohol intake perpetuates pancreatic injury by inhibiting apoptosis and promoting activation of PSCs. Characterisation of the pathways mediating PSC apoptosis has the potential to yield novel therapeutic strategies for chronic pancreatitis.
Publisher: Wiley
Date: 02-1994
Publisher: Wiley
Date: 17-12-2009
DOI: 10.1111/J.1530-0277.2009.01060.X
Abstract: Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.
Publisher: The Endocrine Society
Date: 06-1990
Abstract: A 76-yr-old female with acute pancreatitis and a normal/borderline elevated serum calcium level was found to have an elevated immunoreactive circulating PTH concentration using a C-terminal assay. This high PTH concentration misled the attending physicians and resulted, in retrospect, in an unnecessary neck exploration. When the patient's serum was examined it was found to contain a binding component that bound both C-terminal and PTH-(1-84). This binding component was not retained on a Sep-Pak column and was precipitated by antiserum directed against human immunoglobulin M. The presence of circulating anti-PTH immunoglobulin M explains the apparently high PTH concentrations measured by RIA. The antibodies occurred spontaneously. To the best of our knowledge, this phenomenon has not previously been described.
Publisher: Wiley
Date: 18-08-2008
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1159/000260900
Abstract: Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis. To date, human PSC biology has been studied using cancer- or inflammation-associated (pre-activated) PSCs, but an in vitro model of quiescent normal human PSCs (NhPSCs) has been lacking. To (i) isolate and characterize quiescent NhPSCs, and (ii) evaluate the response of culture-activated NhPSCs to cytokines and LPS. Quiescent NhPSCs were isolated from normal pancreatic tissue using density gradient centrifugation. PSC markers, glial fibrillary acidic protein (GFAP), desmin, α-smooth muscle actin (αSMA) and the lipopolysaccharide (LPS) receptors TLR4 and CD14 were identified by immunoblotting and immunocytochemistry. The effect of platelet-derived growth factor (PDGF), transforming growth factor β (TGFβ) and LPS on NhPSC activation was also assessed. Freshly isolated NhPSCs displayed a polygonal appearance with refringent cytoplasmic lipid droplets. Culture-activated NhPSCs expressed GFAP, desmin, αSMA, TLR4 and CD14, and were responsive to PDGF, TGFβ and LPS. Isolated NhPSCs expressed the same markers as rat PSCs and human cancer-associated PSCs and responded to PDGF and TGFβ similarly to rat PSCs. NhPSC preparations provide a useful in vitro tool to study the biology of PSCs in their physiological, non-activated state. and IAP.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.PAN.2015.02.013
Abstract: The abundant stromal/desmoplastic reaction, a characteristic feature of a majority of pancreatic adenocarcinomas (PDAC), has only recently been receiving some attention regarding its possible role in the pathobiology of pancreatic cancer. It is now well established that the cells predominantly responsible for producing the collagenous stroma are pancreatic stellate cells (PSCs). In addition to extracellular matrix proteins, the stroma also exhibits cellular elements including, immune cells, endothelial cells and neural cells. Evidence is accumulating to indicate the presence of significant interactions between PSCs and cancer cells as well as between PSCs and other cell types in the stroma. The majority of research reports to date, using in vitro and in vivo approaches, suggest that these interactions facilitate local growth as well as distant metastasis of pancreatic cancer, although a recent study using animals depleted of myofibroblasts has raised some questions regarding the central role of myofibroblasts in cancer progression. Nonetheless, novel therapeutic strategies have been assessed, mainly in the pre-clinical setting, in a bid to interrupt stromal-tumour interactions and inhibit disease progression. The next important challenge is for the translation of such pre-clinical strategies to the clinical situation so as to improve the outcome of patients with pancreatic cancer.
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1159/000107399
Publisher: BMJ
Date: 24-11-2011
Publisher: Elsevier
Date: 2015
Publisher: BMJ
Date: 04-2005
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
Location: United States of America
No related grants have been discovered for Jeremy Wilson.