ORCID Profile
0000-0002-6388-8209
Current Organisations
Universitat de les Illes Balears
,
Universidad Complutense de Madrid
,
Hospital Universitari Son Espases
,
Agencia de Calidad Universitaria de las Islas Baleares
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Publisher: Proceedings of the National Academy of Sciences
Date: 17-06-2002
Abstract: The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.
Publisher: Rockefeller University Press
Date: 27-12-2005
DOI: 10.1084/JEM.20050466
Abstract: Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.
Publisher: Informa UK Limited
Date: 10-2022
DOI: 10.2147/JAA.S377174
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.JACI.2006.02.013
Abstract: T lymphocytes (predominantly CD8+ cells) have previously been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We sought to describe the profile of cytokine production by CD8+ and CD4+ cells isolated from bronchoalveolar lavage fluid. Bronchoalveolar lavage was performed in 11 patients with COPD (median FEV1, 63.3% of predicted value) and 9 healthy control subjects. CD8+ and CD4+ T cells were isolated by means of positive selection after macrophage depletion. CD8+ and CD4+ cells were activated with anti-CD3/CD28 antibodies for 60 hours before restimulation with phorbol 12-myristate 13-acetate-ionomycin and brefeldin. Three-color flow cytometry was used to simultaneously measure levels of intracellular cytokines. IL-4 was expressed by a higher percentage of stimulated CD8+ T cells (TC2) compared with CD4+ T cells (TH2) in patients with COPD (P = .01). In contrast, IFN-gamma was expressed in a significantly higher percentage of stimulated CD4+ T cells (TH1) than CD8+ T cells (TC1) in the COPD group (P = .04). TNF-alpha was expressed by almost all TC1 and TH1 cells, with virtually no expression by TC2 and TH2 cells. In addition, a small number of T cells expressing TNF-alpha alone without concomitant IFN-gamma or IL-4 expression were seen in the majority of subjects. There was a higher percentage of TC2 cells in subjects with COPD compared with that seen in the control group (P = .03). Stimulation with anti-CD3/CD28 antibodies increased the percentage of TC2 cells and decreased the percentage of TH2 cells. Our results suggest that there are increased numbers of TC2-like cytokine-expressing cells in the lungs of patients with COPD. These cells might be a source of TH2 cytokines, which might, at least in part, explain the lung eosinophilia associated with COPD exacerbations.
Publisher: Informa UK Limited
Date: 2022
DOI: 10.2147/JAA.S328653
Publisher: Elsevier BV
Date: 2005
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.JAMDA.2017.09.003
Abstract: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. A total of 18,577 patients with COPD [72.0% male mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9% grade 2, 46.6% grade 3, 32.4% and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on in idual disease management. Further validation in prospective studies of these new values are needed.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1157/13070282
Publisher: American Thoracic Society
Date: 15-07-2004
Publisher: Rockefeller University Press
Date: 30-08-2004
DOI: 10.1084/JEM.20040416
Abstract: Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of theophylline can increase HDAC activity. We measured the effect of theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P & 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-α, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, theophylline might restore steroid responsiveness in COPD patients.
Publisher: Wiley
Date: 27-03-2023
DOI: 10.1111/ALL.15711
Abstract: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti‐IgE and anti‐IL5/5R and to compare the effectiveness of both classes of treatment in real life. This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti‐IgE and anti‐IL5/5R. The effectiveness of anti‐IgE and anti‐IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long‐term‐oral corticosteroid (LTOCS) use, asthma‐related emergency room (ER) attendance, and hospital admissions. In the matched analysis ( n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti‐IL5/5R group and 38.7% in the anti‐IgE group. Patients treated with anti‐IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76 95% CI 0.64, 0.89 p 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti‐IgE (37.44% vs. 20.55% reduction p = 0.023). There was some evidence to suggest that patients treated with anti‐IL5/5R experienced fewer asthma‐related hospitalizations (IRR 0.64 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). In real life, both anti‐IgE and anti‐IL5/5R improve asthma outcomes in patients eligible for both biologic classes however, anti‐IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JAIP.2018.08.016
Abstract: The lack of centralized data on severe asthma has resulted in a scarcity of information about the disease and its management. The development of a common data collection tool for the International Severe Asthma Registry (ISAR) will enable standardized data collection, subsequently enabling data interoperability. To create a standardized list of variables for the first international registry for severe asthma via expert consensus. A modified Delphi process was used to reach consensus on a minimum set of variables to capture in ISAR: the core variables. The Delphi panel brought together 27 international experts in the field of severe asthma research. The process consisted of 3 iterative rounds. In each round, all Delphi panel members were issued an electronic ISAR Delphi workbook to complete and return to the ISAR Delphi administrator. Workbooks and result summaries were anonymously distributed by the Delphi administrator to all panel members at subsequent rounds. Finalization of the core variable list was facilitated by 2 face-to-face meetings. Of the initial 747 selected variables, the Delphi panel reached a consensus on 95. The chosen variables will allow severe asthma to be assessed against patient demographics and medical history, patient-reported outcomes, diagnostic information, and clinical characteristics. Physician-reported outcomes such as nonadherence and information about treatment and management strategies will also be recorded. This is the first global attempt to generate an ISAR using a common set of core variables to ensure that data collected across all participating countries are standardized.
Publisher: Massachusetts Medical Society
Date: 12-05-2005
DOI: 10.1056/NEJMOA041892
Publisher: Mary Ann Liebert Inc
Date: 2005
Abstract: Gene expression, at least in part, is regulated by changes in histone acetylation status induced by activation of the proinflammatory redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). Hyperacetylated histone is associated with open actively transcribed DNA and enhanced inflammatory gene expression. In contrast, hypoacetylated histone is linked to a closed repressed DNA state and a lack of gene expression. The degree of inflammatory gene expression is a result of a balance between histone acetylation and histone deacetylation. One of the major mechanisms of glucocorticoid function is to recruit histone deacetylase enzymes to the site of active gene expression, thus reducing inflammation. Oxidative stress can enhance inflammatory gene expression by further stimulating AP-1- and NF-kappaB-mediated gene expression and elevating histone acetylation. In addition, oxidants can reduce glucocorticoid function by attenuating histone deacetylase activity and expression. Thus, oxidant stress, acting through changes in chromatin structure, can enhance inflammation and induce a state of relative glucocorticoid insensitivity. This may account for the lack of glucocorticoid sensitivity in patients with chronic obstructive pulmonary disease. Antioxidants should reduce the inflammation and restore glucocorticoid sensitivity in these subjects.
Publisher: Elsevier BV
Date: 08-2001
Location: United Kingdom of Great Britain and Northern Ireland
Location: Spain
No related grants have been discovered for Borja G Cosio.