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Peter J Barnes - One of the best experts on this subject based on the ideXlab platform.
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rhinovirus infection causes Steroid Resistance in airway epithelium through nuclear factor κb and c jun n terminal kinase activation
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Alberto Papi, Marco Contoli, Luminita A Stanciu, Ian M Adcock, Cinzia M Bellettato, Anna Padovani, Paolo Casolari, Peter J Barnes, Sebastian L JohnstonAbstract:Background Although inhaled glucocorticoids are the mainstays of asthma treatment, they are poorly effective at treating and preventing virus-induced asthma exacerbations. The major viruses precipitating asthma exacerbations are rhinoviruses. Objective We sought to evaluate whether rhinovirus infection interferes with the mechanisms of action of glucocorticoids. Methods Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) α nuclear translocation, glucocorticoid response element (GRE) binding, and transactivation/transrepression functional readouts were evaluated by using immunocytochemistry, Western blotting, DNA binding assays, real-time quantitative PCR, coimmunoprecipitation, and ELISA techniques. Specific inhibitors of c-Jun N-terminal kinase (JNK) and of IκB kinase (IKK) were used to investigate the involvement of intracellular signaling pathways. Results RV-16 infection impaired dexamethasone-dependent (1) inhibition of IL-1β–induced CXCL8 release, (2) induction of mitogen-activated protein kinase phosphatase 1 gene expression, and (3) binding of GR to GREs in airway epithelial cells. This was associated with impaired GRα nuclear translocation, as assessed by means of both immunochemistry (54.0% ± 6.8% vs 24.7% ± 3.8% GR-positive nuclei after 10 nmol/L dexamethasone treatment in sham- or RV-16–infected cells, respectively; P Conclusion RV-16 infection of human airway epithelium induces glucocorticoid Resistance. Inhibition of RV-16–induced JNK and nuclear factor κB activation fully reversed rhinovirus impairment of both GRα nuclear translocation and the transactivation/transrepression activities of glucocorticoids.
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corticoSteroid Resistance in patients with asthma and chronic obstructive pulmonary disease
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Peter J BarnesAbstract:Reduced responsiveness to the anti-inflammatory effects of corticoSteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to Steroid Resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced Steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticoSteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of Steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing Steroid Resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse Steroid Resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase Steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of Steroid Resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments.
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histone deacetylation an important mechanism in inflammatory lung diseases
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2005Co-Authors: Ian M Adcock, Kazuhiro Ito, Peter J BarnesAbstract:Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticoSteroid therapy. CorticoSteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticoSteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and Resistance to the actions of corticoSteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the Steroid Resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse Steroid Resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
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Steroid Resistance in asthma
QJM: An International Journal of Medicine, 1995Co-Authors: Peter J Barnes, Ian M AdcockAbstract:Resistance to the anti-inflammatory effects of glucocorticoids in asthma and other inflammatory and immune diseases is uncommon, but presents a management problem. Understanding the mechanisms of Steroid Resistance provides new insights into the mechanism of Steroid action as well as the underlying chronic disease process. In patients with primary Steroid-resistant (SR) asthma there is no abnormality in the pharmacokinetics of the exogenous Steroid and no significant defect in Steroid binding to the glucocorticoid receptor (GR). Recent studies have demonstrated a marked reduction in the binding of GR to DNA; this appears to be due to increased binding of GR to the transcription factor activator protein-1 (AP-1). Secondary Steroid Resistance in asthma may arise in response to the release of cytokines that activate AP-1 and other transcription factors that bind directly to GR. A similar effect may also be seen with high concentrations of beta 2-agonists that activate another GR binding transcription factor, CREB. Several existing and novel treatment strategies are possible in the management of SR asthma.
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differences in binding of glucocorticoid receptor to dna in Steroid resistant asthma
Journal of Immunology, 1995Co-Authors: Ian M Adcock, Stephen J Lane, Carolanne R Brown, Matthew J Peters, Tak H Lee, Peter J BarnesAbstract:Although glucocorticoSteroids are a very effective treatment for asthma and other chronic inflammatory diseases, a small proportion of patients are resistant to their therapeutic effects. The molecular mechanism for this Steroid Resistance is unclear. Steroid Resistance cannot be explained by pharmacokinetic mechanisms, by a defect in the binding of Steroids to glucocorticoid receptors, nor by defective nuclear translocation of this receptor, thereby suggesting that the molecular abnormality lies distal to nuclear translocation. We examined the ability of nuclear translocated glucocorticoid receptors to bind to their DNA binding sites (GRE) using electrophoretic mobility shift assays in PBMC from patients with Steroid-sensitive and Steroid-resistant asthma. The binding of the glucocorticoid receptor to DNA in these patients was also studied using Scatchard analysis. Dexamethasone induced a significant rapid and sustained twofold increase in GRE binding in PBMCs from Steroid-sensitive asthmatic patients and nonasthmatic individuals, but this was markedly reduced in Steroid-resistant asthmatic patients. Scatchard analysis of glucocorticoid receptor-GRE binding showed no change in binding affinity but did show a reduced number of receptors available for DNA binding in the Steroid-resistant patients. These results suggest that the ability of the glucocorticoid receptor to bind to GRE is impaired in Steroid-resistant patients because of a reduced number of receptors available for binding to DNA.
Ian M Adcock - One of the best experts on this subject based on the ideXlab platform.
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rhinovirus infection causes Steroid Resistance in airway epithelium through nuclear factor κb and c jun n terminal kinase activation
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Alberto Papi, Marco Contoli, Luminita A Stanciu, Ian M Adcock, Cinzia M Bellettato, Anna Padovani, Paolo Casolari, Peter J Barnes, Sebastian L JohnstonAbstract:Background Although inhaled glucocorticoids are the mainstays of asthma treatment, they are poorly effective at treating and preventing virus-induced asthma exacerbations. The major viruses precipitating asthma exacerbations are rhinoviruses. Objective We sought to evaluate whether rhinovirus infection interferes with the mechanisms of action of glucocorticoids. Methods Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) α nuclear translocation, glucocorticoid response element (GRE) binding, and transactivation/transrepression functional readouts were evaluated by using immunocytochemistry, Western blotting, DNA binding assays, real-time quantitative PCR, coimmunoprecipitation, and ELISA techniques. Specific inhibitors of c-Jun N-terminal kinase (JNK) and of IκB kinase (IKK) were used to investigate the involvement of intracellular signaling pathways. Results RV-16 infection impaired dexamethasone-dependent (1) inhibition of IL-1β–induced CXCL8 release, (2) induction of mitogen-activated protein kinase phosphatase 1 gene expression, and (3) binding of GR to GREs in airway epithelial cells. This was associated with impaired GRα nuclear translocation, as assessed by means of both immunochemistry (54.0% ± 6.8% vs 24.7% ± 3.8% GR-positive nuclei after 10 nmol/L dexamethasone treatment in sham- or RV-16–infected cells, respectively; P Conclusion RV-16 infection of human airway epithelium induces glucocorticoid Resistance. Inhibition of RV-16–induced JNK and nuclear factor κB activation fully reversed rhinovirus impairment of both GRα nuclear translocation and the transactivation/transrepression activities of glucocorticoids.
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Steroid Resistance in severe asthma current mechanisms and future treatment
Current Pharmaceutical Design, 2011Co-Authors: Andrew L Durham, Ian M Adcock, Omar TlibaAbstract:The disproportionate cost of treating asthmatic patients who do not respond to conventional anti-inflammatory therapies makes delineation of the mechanism for glucocorticoid Resistance an important field of asthma research. Unbiased cluster analysis indicates that asthma is a syndrome with a number of distinct phenotypes and 5-10% of asthmatics fall into this category of relative glucocorticoid insensitivity. This sub-population is itself divided into smaller subsets which have different underlying mechanisms for this relative glucocorticoid Resistance ranging from an inherited genetic basis to specific kinase signalling pathways triggered by exposure to environmental stressors such as cigarette smoking or infection. Whilst the underlying mechanisms are becoming better understood there remains a lack of effective novel therapies. However it is clear that relative glucocorticoid insensitive patients who are smokers should be encouraged to quit, thereby reducing their oxidant load. Novel treatments will consist of either developing new anti-inflammatory treatments targeting pathways aberrantly activated in these patients or of suppressing signalling pathways that attenuate glucocorticoid receptor function and thereby restoring glucocorticoid sensitivity. It will be important to uncover non-invasive biomarkers for aberrant pathway activation and for discerning which components of glucocorticoid receptor activation are abnormal if future treatments are to be tailored to address these specific issues. Conventional combination therapies will continue to be used in the near future but additional add-on treatments using drugs directed against aberrantly expressed inflammatory pathways or mediators along with an inhaled glucocorticoid are likely to prove the most effective new therapies in the future.
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Steroid Resistance in asthma mechanisms and treatment options
Current Allergy and Asthma Reports, 2008Co-Authors: Ian M Adcock, Paul Ford, Pank Bhavsar, Tehireem Ahmad, Kian Fan ChungAbstract:Glucocorticoid insensitivity presents a profound management problem in patients with asthma because conventional therapies are not effective. Glucocorticoids, acting through the glucocorticoid receptor (GR), are able to selectively repress inflammatory gene expression by utilizing several distinct mechanisms targeting nuclear factor-κB and activator protein-1 activation complexes and by effects on mitogen-activated protein kinases. Different model systems often activate distinct sets of signaling molecules and different glucocorticoid responsiveness may result from differences in concentrations and timing of Steroid treatment of cells, GR expression levels, and the precise inflammatory stimulus used. Thus, abnormal activation of many signaling pathways may affect corticoSteroid responsiveness in patients with corticoSteroid-resistant asthma. Understanding the molecular mechanisms of GR action and inaction may lead to the development of new anti-inflammatory drugs or enable clinicians to reverse the relative Steroid-insensitivity that is characteristic of some patients with severe asthma.
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oxidative stress and Steroid Resistance in asthma and copd pharmacological manipulation of hdac 2 as a therapeutic strategy
Expert Opinion on Therapeutic Targets, 2007Co-Authors: John A Marwick, Ian M Adcock, Kazuhiro Ito, Paul KirkhamAbstract:Insensitivity to corticoSteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticoSteroid efficacy. Recent advances in the understanding of both the mechanisms of corticoSteroid action and corticoSteroid insensitivity have provided hope for a therapeutic strategy of restoring corticoSteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticoSteroid action and is reduced in many cases of Steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds; methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticoSteroid function. Low, subbronchodilator doses of theophylline can also act as corticoSteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticoSteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticoSteroid insensitivity in the future.
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histone deacetylation an important mechanism in inflammatory lung diseases
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2005Co-Authors: Ian M Adcock, Kazuhiro Ito, Peter J BarnesAbstract:Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticoSteroid therapy. CorticoSteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticoSteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and Resistance to the actions of corticoSteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the Steroid Resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse Steroid Resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
Qutayba Hamid - One of the best experts on this subject based on the ideXlab platform.
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microbial superantigens induce glucocorticoid receptor β and Steroid Resistance in a nasal explant model
Laryngoscope, 2004Co-Authors: Samer Fakhri, Meri K Tulic, Pota Christodoulopoulos, Motonori Fukakusa, Saul Frenkiel, Donald Y M Leung, Qutayba HamidAbstract:Objective: To study the role of superantigen (SAg) in inducing glucocorticoid (GC) receptor β and Steroid Resistance in an explant model of nasal tissue. Methods: Nasal tissue was obtained from inferior turbinates of controls and ragweed (RW)-sensitive patients. Tissue samples were incubated with SAg of staphylococcal enterotoxin B. In addition, tissue samples from RW-sensitive patients were incubated with RW allergen in the presence and absence of both SAg and dexamethasone (DEX). The expression of GC receptor β was assessed by immunocytochemistry. The expression of interleukin (IL)-2 and IL-4 mRNA was assessed by in situ hybridization. Results: SAg induced an increase in the expression of GC receptor β in atopic tissue and to a lesser extent in nonatopic tissue. The most significant induction of GC receptor β was observed in response to SAg and RW in atopic tissue. Stimulation of atopic tissue with RW alone and SAg alone induced IL-4 and IL-2 mRNA, respectively. Incubation of atopic tissue with both SAg and RW induced both IL-2 and IL-4 mRNA. The increase in IL-4 mRNA expression was blunted by the addition of DEX to atopic tissue stimulated with RW alone but not to tissue stimulated by both RW and SAg. Conclusion: Our results demonstrate that SAgs induce Steroid Resistance in atopic nasal explant tissue by up-regulating the expression of GC receptor β. Furthermore, we have shown that the up-regulation of GC receptor β is a local event that is associated with the coexpression of IL-2 and IL-4 mRNA.
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microbial superantigens induce glucocorticoid receptor β and Steroid Resistance in a nasal explant model
Laryngoscope, 2004Co-Authors: Samer Fakhri, Meri K Tulic, Pota Christodoulopoulos, Motonori Fukakusa, Saul Frenkiel, Donald Y M Leung, Qutayba HamidAbstract:Objective To study the role of superantigen (SAg) in inducing glucocorticoid (GC) receptor beta and Steroid Resistance in an explant model of nasal tissue. Methods Nasal tissue was obtained from inferior turbinates of controls and ragweed (RW)-sensitive patients. Tissue samples were incubated with SAg of staphylococcal enterotoxin B. In addition, tissue samples from RW-sensitive patients were incubated with RW allergen in the presence and absence of both SAg and dexamethasone (DEX). The expression of GC receptor beta was assessed by immunocytochemistry. The expression of interleukin (IL)-2 and IL-4 mRNA was assessed by in situ hybridization. Results SAg induced an increase in the expression of GC receptor beta in atopic tissue and to a lesser extent in nonatopic tissue. The most significant induction of GC receptor beta was observed in response to SAg and RW in atopic tissue. Stimulation of atopic tissue with RW alone and SAg alone induced IL-4 and IL-2 mRNA, respectively. Incubation of atopic tissue with both SAg and RW induced both IL-2 and IL-4 mRNA. The increase in IL-4 mRNA expression was blunted by the addition of DEX to atopic tissue stimulated with RW alone but not to tissue stimulated by both RW and SAg. Conclusion Our results demonstrate that SAgs induce Steroid Resistance in atopic nasal explant tissue by up-regulating the expression of GC receptor beta. Furthermore, we have shown that the up-regulation of GC receptor beta is a local event that is associated with the coexpression of IL-2 and IL-4 mRNA.
William E Smoyer - One of the best experts on this subject based on the ideXlab platform.
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plasma cytokine profiling to predict Steroid Resistance in pediatric nephrotic syndrome
Kidney International Reports, 2021Co-Authors: Shipra Agrawal, Michael E Brier, William E Smoyer, Bryce A KerlinAbstract:Introduction Glucocorticoids (GCs) are the primary treatment for nephrotic syndrome (NS), although ∼10% to 20% of children develop Steroid-resistant NS (SRNS). Unfortunately, there are no validated biomarkers able to predict SRNS at initial disease presentation. We hypothesized that a plasma cytokine panel could predict SRNS at disease presentation, and identify potential pathways regulating SRNS pathogenesis. Methods Paired plasma samples were collected from 26 children with Steroid-sensitive NS (SSNS) and 14 with SRNS at NS presentation and after ∼7 weeks of GC therapy, when SSNS versus SRNS was clinically determined. Plasma cytokine profiling was performed with a panel of 27 cytokines. Results We identified 13 cytokines significantly different in Pretreatment SSNS versus SRNS samples. Statistical modeling identified a cytokine panel (interleukin [IL]-7, IL-9, monocyte chemoattractant protein–1 [MCP-1]) able to discriminate between SSNS and SRNS at disease presentation (receiver operating characteristic [ROC] value = 0.846; sensitivity = 0.643; specificity = 0.846). Furthermore, GC treatment resulted in significant decreases in plasma interferon-γ (IFN-γ), tumor necrosis factor–α (TNF-α), IL-7, IL-13, and IL-5 in both SSNS and SRNS patients. Conclusions These studies suggest that initial GC treatment of NS reduces the plasma cytokines secreted by both CD4+ TH1 cells and TH2 cells, as well as CD8+ T cells. Importantly, a panel of 3 cytokines (IL-7, IL-9, and MCP-1) was able to predict SRNS prior to GC treatment at disease presentation. Although these findings will benefit from validation in a larger cohort, the ability to identify SRNS at disease presentation could greatly benefit patients by enabling both avoidance of unnecessary GC-induced toxicity and earlier transition to more effective alternative treatments.
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treatment outcome of late Steroid resistant nephrotic syndrome a study by the midwest pediatric nephrology consortium
Pediatric Nephrology, 2013Co-Authors: Caroline Straatmann, Rose Ayoob, Rasheed Gbadegesin, Keisha Gibson, Michelle N Rheault, Tarak Srivastava, Cheryl L Tran, Debbie S Gipson, Larry A Greenbaum, William E SmoyerAbstract:Background Idiopathic nephrotic syndrome (NS) in children is classified as Steroid sensitive or Steroid resistant. Steroid sensitivity typically portends a low risk of permanent renal failure. However, some initially Steroid-sensitive patients later develop Steroid Resistance. These patients with late Steroid Resistance (LSR) are often treated with immunosuppressant medications, but the effect of these additional drugs on the long-term prognosis of LSR is still unknown.
Kazuhiro Ito - One of the best experts on this subject based on the ideXlab platform.
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oxidative stress and Steroid Resistance in asthma and copd pharmacological manipulation of hdac 2 as a therapeutic strategy
Expert Opinion on Therapeutic Targets, 2007Co-Authors: John A Marwick, Ian M Adcock, Kazuhiro Ito, Paul KirkhamAbstract:Insensitivity to corticoSteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticoSteroid efficacy. Recent advances in the understanding of both the mechanisms of corticoSteroid action and corticoSteroid insensitivity have provided hope for a therapeutic strategy of restoring corticoSteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticoSteroid action and is reduced in many cases of Steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds; methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticoSteroid function. Low, subbronchodilator doses of theophylline can also act as corticoSteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticoSteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticoSteroid insensitivity in the future.
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histone deacetylation an important mechanism in inflammatory lung diseases
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2005Co-Authors: Ian M Adcock, Kazuhiro Ito, Peter J BarnesAbstract:Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticoSteroid therapy. CorticoSteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticoSteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and Resistance to the actions of corticoSteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the Steroid Resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse Steroid Resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
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cigarette smoke activates human monocytes by an oxidant ap 1 signaling pathway implications for Steroid Resistance
Molecular Pharmacology, 2005Co-Authors: Matthew Walters, Ian M Adcock, Kazuhiro Ito, Mark J Paulclark, Shaun K Mcmaster, Jane A MitchellAbstract:Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smoking-induced pathophysiology is often resistant to the anti-inflammatory effects of glucocorticoids. The nature of cigarette smoke-induced inflammation is still not defined, although neutrophil recruitment and activation seem to be consistent features. In the current study, we have used a range of approaches to demonstrate that cigarette smoke activates human monocytes and macrophages to release the CXC chemokine CXCL8 [(interleukin-8 (IL-8)]. Furthermore, we show for the first time that cigarette smoke synergizes with proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha, and it is this interaction that confers Steroid Resistance to smoke-induced CXCL8 release. We go on to show that smoke-induced activation of human cells is an oxidant-mediated phenomenon acting through activator protein-1, but not nuclear factor kappaB, pathway. These observations add significantly to our understanding of smoke as an inflammatory stimulus that has implications for potential the development of treatments of smoking or related disease.
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histone acetylation and deacetylation importance in inflammatory lung diseases
European Respiratory Journal, 2005Co-Authors: Pete J Arnes, Ia M Adcock, Kazuhiro ItoAbstract:Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappa B. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticoSteroid therapy. CorticoSteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and Resistance to the actions of corticoSteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the Steroid Resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse Steroid Resistance in chronic obstructive pulmonary disease and other inflammatory diseases.
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Steroid Resistance in asthma a major problem requiring novel solutions or a non issue
Current Opinion in Pharmacology, 2004Co-Authors: Ian M Adcock, Kazuhiro ItoAbstract:Abstract Steroid insensitivity in severe asthma is rare but has huge health care costs. Thus, 5% of asthmatic patients account for ∼50% of total health care costs. Incorrect diagnosis, non-compliance with therapy and psychological problems are all confounding issues, and can account for a failure to respond to Steroids in many of these patients. A recent report (ENFUMOSA) has suggested that severe asthma, of which Steroid-resistant asthma is a component, consists of at least one, possibly more, distinct disease(s) with differing pathologies. Future studies such as Bio-Air and TENOR could confirm this; therefore, it is not surprising that well-characterised Steroid-resistant and Steroid-dependent asthma have multiple mechanisms to account for a lack of Steroid sensitivity, including defective ligand binding to the Steroid receptor, abnormal receptor nuclear translocation and abnormal association with pro-inflammatory nuclear proteins. Distinct treatments might have to be tailored to the individual patient; for example, drugs that enhance receptor nuclear translocation will only be effective in patients in whom this is a problem. Once issues of diagnosis, compliance and psychological disorders have been resolved, true Steroid Resistance or dependence is unlikely to be an issue for most clinicians, who will rarely, if ever, see these patients. However, management of those few patients with true Steroid Resistance will require novel therapies tailored to specific subgroups of patients.