1,721,294 research outputs found
Kinase targets and inhibitors for the treatment of airway inflammatory diseases: the next Generation of drugs for severe asthma and COPD?
No full textKinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function, and in airway remodeling. Important pro-inflammatory transcription factors such as activating protein-1 and nuclear factor kappaB, which are activated in airway disease, require kinase activation to switch on inflammatory genes, while other kinases can regulate mRNA half-life. Selective kinase inhibitors have been developed that reduce inflammatory gene expression and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or overactive in disease should allow for selective treatment of airway inflammatory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukemia viral oncogene homolog tyrosine kinase inhibitor, imatinib mesylate, in the treatment of chronic myelogenous leukemia. Encouraging data from animal models and primary cells and early phase I and II studies in other diseases suggest that inhibitors of p38 mitogen-activated protein kinase and inhibitor of kappaB kinase-2 may prove to be useful novel therapies in the treatment of severe asthma and chronic obstructive pulmonary disease
Chemokines and asthma.
No full textThe migration of cells towards and into the site of an inflammatory insult is critical for maintenance of the inflammatory response and its resolution. This is particularly so in the case of asthma where recruitment of key effector cells may control disease severity, responsiveness to current therapies and the airway remodelling associated with the disease. Chemokine receptor antagonists have the hope of preventing inflammatory cell recruitment to the airway and perhaps as a consequence affect the resolution of airway remodelling. A number of selective antagonists directed at various CC and CXC receptors thought to be important in asthma are currently at various stages of clinical development. Results from these studies will determine whether chemokine receptor antagonists will prove beneficial in severe glucocorticoid-dependent and -resistant asthmatic subjects. Furthermore, it is possible that early treatment with these agents may prevent the disease from becoming established
Pharmacology of airway inflammation in asthma and COPD
No full textThe current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term treatment. Although inhaled glucocorticoids are highly effective in controlling airway inflammation in asthma, they are ineffective in the small group of patients with glucocorticoid-dependent and -resistant asthma. With very few exceptions, COPD is caused by tobacco smoking, and smoking cessation is the only truly effective treatment of COPD available. Current pharmacological treatment of COPD is unsatisfactory, as it does not significantly influence the severity of the disease or its natural course. Glucocorticoids are scarcely effective in COPD patients without concomitant asthma. Bronchodilators improves symptoms and quality of life, in COPD patients, but, with the exception of tiotropium, they do not significantly influence the natural course of the disease. Theophylline is the only drug which has been demonstrated to have a significant effect on airway inflammation in patients with COPD. Here we review the pharmacology of currently used antiinflammatory therapies for asthma and COPD and their proposed mechanisms of action. Recent understanding of disease mechanisms in severe steroid-dependent and -resistant asthma and in COPD, has lead to the development of novel compounds, which are in various stages of clinical development. We review the current status of some of these new potential drugs
Cross-talk between pro-inflammatory transcription factors and glucocorticoids
No full textAsthma is a chronic inflammatory disease of the airway that is characterized by cellular infiltration and activation. These processes are induced by overexpression of chemokines and cytokines, such as eotaxin, IL-1β and GM-CSF. These mediators are downstream targets for the transcription factors activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), which control the expression of most immunomodulatory genes and whose activity and expression are elevated in asthma. Glucocorticoids are the most effective anti-inflammatory drugs used in the treatment of chronic inflammatory diseases such as asthma. They act by binding to a specific glucocorticoid receptor (GR) that on activation translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) the expression of responsive genes. Transrepression is the major mechanism of glucocorticoid action in inhibiting inflammatory gene expression. Thus, the ability of the transciption factors AP-1 and NF-κB to induce gene transcription is attenuated by GR. Although only 5-10% of asthmatic subjects are glucocorticoid-insensitive, these subjects account for over 50% of the health-care costs for asthma (> $6 billion per annum). Examining these patients also gives an insight into important aspects of glucocorticoid action in controlling inflammation and into the development of potential new drugs. Biochemical and genomic studies have indicated abnormal induction of the c-Jun N-terminal kinase (JNK) pathway in some of these patients. The ability of most patients to respond to dexamethasone with induction of histone acetylation correlated with nuclear translocation of GR. However, a subgroup of these patients had an inability to correctly interact with the basal transcription complex in spite of high levels of nuclear GR. This suggests that cross-talk between pro- and anti-inflammatory transcription factors may modulate activation of the transcriptional complex and thereby reduce steroid actions
Cross-talk between pro-inflammatory transcription factors and glucocorticoids
No full textAsthma is a chronic inflammatory disease of the airway that is characterized by cellular infiltration and activation. These processes are induced by overexpression of chemokines and cytokines, such as eotaxin, IL-1beta and GM-CSF. These mediators are downstream targets for the transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which control the expression of most immunomodulatory genes and whose activity and expression are elevated in asthma. Glucocorticoids are the most effective anti-inflammatory drugs used in the treatment of chronic inflammatory diseases such as asthma. They act by binding to a specific glucocorticoid receptor (GR) that on activation translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) the expression of responsive genes. Transrepression is the major mechanism of glucocorticoid action in inhibiting inflammatory gene expression. Thus, the ability of the transcription factors AP-1 and NF-kappaB to induce gene transcription is attenuated by GR. Although only 5-10% of asthmatic subjects are glucocorticoid-insensitive, these subjects account for over 50% of the health-care costs for asthma (> $6 billion per annum). Examining these patients also gives an insight into important aspects of glucocorticoid action in controlling inflammation and into the development of potential new drugs. Biochemical and genomic studies have indicated abnormal induction of the c-Jun N-terminal kinase (JNK) pathway in some of these patients. The ability of most patients to respond to dexamethasone with induction of histone acetylation correlated with nuclear translocation of GR. However, a subgroup of these patients had an inability to correctly interact with the basal transcription complex in spite of high levels of nuclear GR. This suggests that cross-talk between pro- and anti-inflammatory transcription factors may modulate activation of the transcriptional complex and thereby reduce steroid actions
Transcription factors in asthma and COPD
No full textInflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD) and both are characterized by an increased transcription of pro-inflammatory proteins (eg, cytokines, chemokines, growth factors and enzymes). Changes in inflammatory gene transcription are regulated by transcription factors that may therefore play a key role in the pathogenesis of asthma and COPD by amplifying and perpetuating the inflammatory process, and thereby contributing to disease severity and responsiveness to treatment. Several new compounds based on interactions with specific transcription factors or their activation pathways are now in development for the treatment of asthma and COPD
Clinical definition of COPD exacerbations and classification of their severity
No full textA standardized definition of chronic obstructive pulmonary disease (COPD) exacerbation still represents an unmet need in respiratory medicine; definitions currently rely on clinical empiricism with little evidence-based scientific support. Exacerbations of COPD are certainly clear events in the mind of practicing physicians. However, when one tries to provide simple concepts such as their definition and classification of severity, one realizes how little we know. Current symptom- and event-based definitions of a COPD exacerbation, as well as the classifications of the severity of COPD exacerbations, all have their own limitations. Efforts to assess the efficacy of new therapies in the treatment and prevention of COPD exacerbations have been hampered by the lack of a widely agreed upon and consistently used definition. There is a need for greater investment in research on COPD exacerbations in order to promote a better understanding of COPD exacerbations
Targeting Th2 cells in asthmatic patients
No full textThe most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and -resistant asthma still represents a great clinical burden accounting for approximately 50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroid-sparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible individuals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease
Breaking news: DNA damage and repair pathways in COPD and implications for pathogenesis and treatment
No full textNew insights into the molecular mechanisms of corticosteroids actions
No full textCorticosteroids produce a marked improvement in clinical parameters in most asthmatic patients; in contrast, corticosteroids have little effect on lung function measurements in patients with chronic obstructive pulmonary disease. By uncovering the reason for this paradox, it should be possible to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic receptor, which is subjected to post-translational modifications. Receptor phosphorylation may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Other modifications such as nitration/nitrosylation may also affect glucocorticoid receptor function. Oxidative stress due to cigarette smoke may be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription and reduces glucocorticoid receptor-associated repressor functions. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease
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