1,721,067 research outputs found
Chemokine receptor inhibitors as a novel option in treatment of 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. © 2004 Bentham Science Publishers Ltd
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 oil 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 oil COPD exacerbations in order to promote a better understanding of COPD exacerbation
Interactions between long-acting ß2-agonists and glucocorticoids
No full textLong acting ß2-agonists and glucocorticoids together control asthma in ~95% of affected individuals, although symptoms return after treatment is stopped. Treatment of chronic obstructive pulmonary disease (COPD) scarcely influences the natural course of the disease. Neither long-acting ß2-agonists (LABAs) nor glucocorticoids alone significantly influence the course of COPD. Recent evidence suggests that a combination of the two therapies is more promising. It can decrease the exacerbation rates in severe COPD and may also decrease mortality
Interactions between long-acting ß2-agonists and glucocorticoids
No full textLong acting ß2-agonists and glucocorticoids together control asthma in ~95% of affected individuals, although symptoms return after treatment is stopped. Treatment of chronic obstructive pulmonary disease (COPD) scarcely influences the natural course of the disease. Neither long-acting ß2-agonists (LABAs) nor glucocorticoids alone significantly influence the course of COPD. Recent evidence suggests that a combination of the two therapies is more promising. It can decrease the exacerbation rates in severe COPD and may also decrease mortality
Chronic obstructive pulmonary disease and lung cancer: new molecular insights
No full textBoth chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients
New targets for drug development in asthma
No full textAsthma is a chronic inflammatory disease that affects about 300 million people worldwide, a total that is expected to rise to about 400 million over the next 15-20 years. Most asthmatic individuals respond well to the currently available treatments of inhaled corticosteroids and beta-adrenergic agonists; however, 5-10% have severe disease that responds poorly. Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of anti-leucotrienes and the anti-IgE monoclonal antibody omalizumab in some patients. However, more knowledge of the inflammatory mechanisms within the airways is required. Improvements in available therapies-such as the development of fast-onset, once-a-day combination drugs with better safety profiles-will occur. Other drugs, such as inhaled p38 MAPK inhibitors and anti-oxidants, that target specific pathways or mediators could prove useful as monotherapies, but could also, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe asthma. Biological agents directed against the interleukin-13 pathway and new immunoregulatory agents that modulate functions of T-regulatory and T-helper-17 cells are likely to be successful. Patient-specific treatments will depend on the development of discriminatory handprints of distinct asthma subtypes and are probably over the horizon. Although a cure is unlikely to be developed in the near future, a greater understanding of disease mechanisms could bring such a situation nearer to reality
New targets for drug development in asthma
No full textAsthma is a chronic inflammatory disease that affects about 300 million people worldwide, a total that is expected to rise to about 400 million over the next 15-20 years. Most asthmatic individuals respond well to the currently available treatments of inhaled corticosteroids and beta-adrenergic agonists; however, 5-10% have severe disease that responds poorly. Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of anti-leucotrienes and the anti-IgE monoclonal antibody omalizumab in some patients. However, more knowledge of the inflammatory mechanisms within the airways is required. Improvements in available therapies-such as the development of fast-onset, once-a-day combination drugs with better safety profiles-will occur. Other drugs, such as inhaled p38 MAPK inhibitors and anti-oxidants, that target specific pathways or mediators could prove useful as monotherapies, but could also, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe asthma. Biological agents directed against the interleukin-13 pathway and new immunoregulatory agents that modulate functions of T-regulatory and T-helper-17 cells are likely to be successful. Patient-specific treatments will depend on the development of discriminatory handprints of distinct asthma subtypes and are probably over the horizon. Although a cure is unlikely to be developed in the near future, a greater understanding of disease mechanisms could bring such a situation nearer to reality
Strategies for improving the efficacy and therapeutic ratio of glucocorticoids
No full textAlthough glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for example asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future
TRANSCRIPTION FACTORS Overview
No full textThe term ‘transcription factor’ refers to a large family of proteins, which exert transcriptional control via specific interactions with regulatory gene sequences. Here, we provide a summary of the different classes of the transcription factor divided according to their DNA-binding motifs. The modular structure of transcription factors and the presence of distinct interacting domains determine the ability of these factors to associate with each other,, and with coactivating/repressing proteins. By recruiting transcriptional coactivators, transcription factors can induce changes in chromatin structure enabling gene expression to occur. We use the activation of the Rel transcription factor NF-κB and the nuclear receptor GR as examples to indicate some of the intricacies and subtleties of DNA binding, chromatin remodeling, and transcription factor cross-talk. Finally, we review the evidence for the involvement of select transcription factors in allergic and inflammatory diseases of the lung, and how changes in the expression and/or activity of these factors may vary in disease and provide important targets for future drug development
CORTICOSTEROIDS | Glucocorticoid Receptors
No full textCorticosteroids bind to and activate a cytoplasmic glucocorticoid receptor (GR) which exists as several isoforms derived from a single gene product by alternative splicing. The activated glucocorticoid receptor translocates into the nucleus and binds to specific response elements in the promoter regions of anti-inflammatory genes such as lipocortin-1 and secretory leukocyte protease inhibitor. However, the major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor kappa B (NF-κB) and activator protein-1, that mediate the expression of inflammatory genes. NF-κB switches on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. The interactions between NF-κB and the glucocorticoid receptor result in differing effects on histone modifications and subsequent chromatin remodeling. GR is subjected to posttranslational modifications and these may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Therapeutically, drugs that enhance glucocorticoid receptor nuclear translocation (long-acting β-agonists) and GR-associated histone deacetylase activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF-κB preferentially have also been successful in the treatment of allergic disease in the skin
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