Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.
01 Mar 2013-The Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol)-Vol. 131, Iss: 3, pp 636-645
TL;DR: A novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors.
Abstract: 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.
Citations
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TL;DR: How dichotomizing asthma according to levels of type 2 inflammation — into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes) — has shaped the thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 1 inflammation is considered.
Abstract: Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation--into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes)--has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.
1,068 citations
TL;DR: It is important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.
Abstract: Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.
870 citations
TL;DR: In this article, the authors discuss the origin and molecular properties of the glucocorticoid receptor (GR) isoforms and their contribution to the specificity and sensitivity of glucoc corticoid signaling in healthy and diseased tissues.
Abstract: Glucocorticoids are primary stress hormones necessary for life that regulate numerous physiologic processes in an effort to maintain homeostasis. Synthetic derivatives of these hormones have been mainstays in the clinic for treating inflammatory diseases, autoimmune disorders, and hematologic cancers. The physiologic and pharmacologic actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes through direct binding to DNA response elements, physically associating with other transcription factors, or both. The traditional view that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a large cohort of receptor isoforms with unique expression, gene-regulatory, and functional profiles. These GR subtypes are derived from a single gene by means of alternative splicing and alternative translation initiation mechanisms. Posttranslational modification of these GR isoforms further expands the diversity of glucocorticoid responses. Here we discuss the origin and molecular properties of the GR isoforms and their contribution to the specificity and sensitivity of glucocorticoid signaling in healthy and diseased tissues.
730 citations
TL;DR: Pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual P DEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.
Abstract: Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.
630 citations
TL;DR: A number of studies have shown that there is no single "magic bullet" to combat oxidative stress, but instead a combination therapy, targeting oxidative stress in the various subcellular compartments, may prove to be more effective in COPD.
555 citations
References
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TL;DR: This review summarizes the understanding of how glucocorticoids inhibit inflammation and give rise to side effects.
Abstract: Glucocorticoids are among the most common therapeutic agents used in medical practice, yet their mechanisms of action are only partly understood. This review summarizes our understanding of how glu...
2,684 citations
"Corticosteroid resistance in patien..." refers background in this paper
...Phosphodiesterase (PDE) 4 inhibitors are now in clinical development for the treatment of COPD and severe asthma, and oral roflumilast is already marketed as the first anti-inflammatory drug for COPD.86 However, the oral dose is limited by side effects that are also due to PDE4 inhibition, including nausea, diarrhea, and headaches....
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...VOLUME 131, NUMBER 3 BARNES 643 Reversal of steroid resistance is a new strategy to address steroid-resistant inflammation in asthmatic patients and patients with COPD....
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...It is necessary to understand the molecular mechanisms whereby corticosteroids suppress inflammation to understand the various mechanisms of steroid resistance in asthmatic patients and patients with COPD.3,4 Corticosteroids activate several antiinflammatory genes and suppress many inflammatory genes but can also modulate inflammation through additional posttranscriptional mechanisms....
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...Nrf2 activity is markedly reduced in cells from patients with COPD, and this is linked to reduced HDAC2 expression, which normally keeps this protein deacetylated and active.94,95 Sulforaphane is an activator of Nrf2 and has been shown to increase HDAC2 expression and reverse steroid resistance in mice exposed to cigarette smoke and in macrophages from patients with COPD.96 Curcumin (diferuloylmethane), which is found in turmeric spice used in curry, also increases HDAC2 expression after it has been reduced by oxidative stress and at concentrations lower than required for its antioxidant effects.97 Macrolides, including nonantibiotic macrolides, also reverse corticosteroid resistance through inhibition of PI3K pathways but might act more distally in the pathway.98 Inhaled long-acting b2-agonists It is now well established that adding long-acting b2-agonists (LABAs) to ICSs improves asthma control to a greater degree than increasing the dose of ICS....
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...Considerable progress has recently been made in understanding the molecular basis for steroid resistance in both patients with severe asthma and those with COPD....
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TL;DR: It is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations, which has important implications for the development of new therapies.
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations This has important implications for the development of new therapies
1,313 citations
"Corticosteroid resistance in patien..." refers background in this paper
...eosinophils in the airways and more bronchodilator reversibility,(32,33) suggesting that these patients with COPD also have concomitant asthma.(34)...
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TL;DR: Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease, and this work has shown that HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages.
Abstract: Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages. Methods HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-tra...
951 citations
TL;DR: Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, and increased P-glycoprotein-mediated drug efflux.
906 citations
"Corticosteroid resistance in patien..." refers background in this paper
...Steroid resistance is a feature of several severe immune and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosis.(1) Now that the anti-inflammatory mechanisms of actions of corticosteroids are better understood, it has been possible to elucidate the molecular basis of steroid resistance....
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...MOLECULAR MECHANISMS OF STEROID RESISTANCE Several molecular mechanisms contributing to decreased antiinflammatory effects of corticosteroids have been identified in asthmatic patients, many of which have also been described in patients with other inflammatory diseases, including COPD (Table I).(1)...
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TL;DR: Severe asthma is characterized by abnormal lung function that is responsive to bronchodilators, a history of sinopulmonary infections, persistent symptoms, and increased health care utilization.
Abstract: Background Severe asthma causes the majority of asthma morbidity. Understanding mechanisms that contribute to the development of severe disease is important. Objective The goal of the Severe Asthma Research Program is to identify and characterize subjects with severe asthma to understand pathophysiologic mechanisms in severe asthma. Methods We performed a comprehensive phenotypic characterization (questionnaires, atopy and pulmonary function testing, phlebotomy, exhaled nitric oxide) in subjects with severe and not severe asthma. Results A total of 438 subjects with asthma were studied (204 severe, 70 moderate, 164 mild). Severe subjects with asthma were older with longer disease duration ( P P ≤ .0001). Lung function was lower in severe asthma with marked bronchodilator reversibility ( P P = .0007), but blood eosinophils, IgE, and exhaled nitric oxide levels did not differentiate disease severity. A reduced FEV 1 , history of pneumonia, and fewer positive skin tests were risk factors for severe disease. Early disease onset (age P P = .002). Later disease onset (age ≥ 12 years) was associated with lower lung function and sinopulmonary infections ( P ≤ .02). Conclusion Severe asthma is characterized by abnormal lung function that is responsive to bronchodilators, a history of sinopulmonary infections, persistent symptoms, and increased health care utilization. Clinical implications Lung function abnormalities in severe asthma are reversible in most patients, and pneumonia is a risk factor for the development of severe disease.
863 citations
"Corticosteroid resistance in patien..." refers background in this paper
...Patients with severe asthma are less responsive to corticosteroids than thosewithmild asthma, and therefore steroid resistance might be a mechanism contributing to asthma severity.(18) Indeed, asthma severity is largely defined on the basis of the dose of corticosteroids that might be needed to control symptoms....
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