Ian Adcock

..We summarize these known mechanisms at the end of this review...

..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...

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..abstract:..

..The purpose of this meta-analysis is to determine whether eCO is elevated in asthmatics, is regulated by steroid treatment and reflects disease severity and control...

..Some of these new Th2-oriented strategies may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease...

..Here, we examine the role of protein kinase C isoforms and janus activated kinase 2 (JAK2) activation in NF-kappaB activation and LPS-stimulated NO production...

..However, the impact of cigarette smoke exposure on the expression of mSin3a and Mi2alpha/beta and their role in glucocorticoid responsiveness is unknown...

..The aim of the present study was to explore the effects of HDAC inhibitors on apoptosis in human eosinophils and neutrophils...

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..Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new anti-inflammatory drugs or reverse the relative corticosteroid-insensitivity that is characteristic of these diseases...

..This might have important clinical implications, leading to a better understanding of the inflammatory mechanisms of many diseases and might signal the development of new anti-inflammatory treatments in the future...

..Enhanced acetylation of H4K5 and K16 was seen in the PP. These results demonstrate that histone acetylation is associated with inflammation and may provide a novel therapeutic target for mucosal inflammation...

..Thus, elucidation of the cause for the relative lack of corticosteroid response in this subgroup of asthmatic individuals may have important implications for other diseases...

..Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease...

..Targeting specific enzymes involved in this process may lead to new therapeutic agents, in particular, in situations where current anti-inflammatory therapies are currently suboptimal...

..Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new antiinflammatory drugs or may reverse the relative steroid insensitivity that is characteristic of patients with these diseases...

..However, management of those few patients with true steroid resistance will require novel therapies tailored to specific subgroups of patients...

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..Although there are concerns over the long-term safety of these agents, they may prove useful particularly in situations where current anti-inflammatory therapies are suboptimal...

..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...

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..Furthermore, it is possible that early treatment with these agents may prevent the disease from becoming established...

..Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease...

..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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..These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease...

..Histone modifications, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of "epigenetic therapies" for disease...

..More evidence is required concerning the long-term safety of these agents, for example, lung destruction, and in comparison with currently used therapies...

..We conclude that H(2)O(2) prolongs NF-kappaB activation in co-stimulated cells by suppressing the negative regulatory functions of Cezanne and IkappaBalpha...

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..We investigated whether human airway smooth muscle cells could express and secrete MMP-12, thereby participating in the pathogenesis of airway inflammatory diseases...

..This further suggests that pharmacological manipulation of of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases...

..These data also suggest that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases...

..Exposure of mice to ozone for 6 wk induced a chronic inflammatory process, with alveolar enlargement and damage linked to epithelial apoptosis and increased protease expression...

..This suggests that cross-talk between pro- and anti-inflammatory transcription factors may modulate activation of the transcriptional complex and thereby reduce steroid actions...

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..We review the current status of some of these new potential drugs...

..Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma...

..These data show that detection of acetylated histone residues at the single cell level using FACs may be a powerful new tool for the analysis of modulation of cell proliferation and gene transcription...

..Understanding how corticosteroids work in asthma may help in designing novel corticosteroids with fewer systemic effects, as well as novel anti-inflammatory approaches...

..Treatments may be targeted to patients with specific mechanisms...

..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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..This novel mechanism of inflammation may be important in increasing the severity and chronicity of inflammatory diseases...

..These data suggest that the mechanism of glucocorticoid action in suppressing interleukin-1 beta-stimulated GM-CSF release in A549 cells may involve modulation of CBP-mediated histone-acetylase activity and DNA methylation...

..This defect does not appear to be due to a reduced expression of GR but may be associated with a failure of GR to translocate into the nucleus and/or a reduced ability to inhibit AP-1 actions...

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..We propose that FE(NO) is associated with eosinophilic inflammation in children with difficult asthma, following prednisolone, and may help in identifying patients in whom persistent symptoms are associated with airway eosinophilia...

..Changes in histone acetylation at the IL-8 are important in its regulation by proinflammatory and anti-inflammatory agents, and modulation of this activity may have therapeutic potential in inflammatory conditions...

..Many of the detrimental side-effects of corticosteroids are believed to be due to gene induction, leading to the search for novel corticosteroids which can repress inflammatory genes without inducing gene transcription...

..PMA induced a rapid and prolonged increase in c-Fos and c-Jun nuclear localization, which was not attenuated by co-incubation with dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)..

..This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines...

..In this study, we show that the -509T variant on haplotype 1 is the most informative marker of the TGFbeta1 contribution to asthma severity...

..The important outcome of this is that new preventive and curative treatments may ensue...

..We suggest that by this mechanism high doses of inhaled beta 2-adrenoceptor agonists may inhibit the anti-inflammatory effects of endogenous glucocorticoids and exogenous corticosteroids used for asthma therapy...

..The short-acting nature of salmeterol, when administered systemically, and the reduction in beta-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective beta-adrenoceptor agonist...

..These data are consistent with negative feed-back involving down-regulation of NF-kappaB by de novo IkappaB alpha synthesis and suggest that JNK activation may also be down-regulated by a cycloheximide sensitive process...

..Collectively, these data clearly demonstrate the expression of multiple PKC isoenzymes in human lung and tracheal smooth muscle, suggesting that they subserve diverse multifunctional roles in these tissues...

..CONCLUSION: Our study suggests that the bronchial epithelium is not a source of IL-10 and cannot respond to exogenous IL-10 because of a lack of IL-10R expression...

..We conclude that IL-1beta stimulates PG production via transcriptional activation of COX-2 and provide evidence that this may involve NF-kappaB...

..As eotaxin stimulates human eosinophils, this chemokine and related molecules may be involved in human diseases such as asthma where eosinophil accumulation is a prominent feature...

..This provides a means whereby allergen exposure leads to the expression of Th2 cytokines, and this novel mechanism may provide new approaches to treating allergic diseases...

..Targeting specific enzymes involved in this process might lead to new therapeutic agents, particularly in situations in which current anti-inflammatory therapies are suboptimal...

..Glucocorticoids and IL-1beta or TNF-alpha modulate GRO-alpha release partly through the inhibition of JNK pathway, resulting from an up-regulation of MKP-1 expression...

..Further appreciation of the role of these changes may lead to the development of novel therapeutic approaches to inflammatory lung diseases that are currently difficult to treat...

..Inhibition of JNK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and AHR...

..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...

..Therefore, ozone may induce murine AHR and neutrophilic inflammation through the activation of the Toll-like receptor pathway that may sense noninfectious stimuli such as oxidative stress...

..This review summarizes the various hypotheses underlying corticosteroid insensitivity in smoking asthmatics and discusses the development of potential novel therapies based on these concepts...

..Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function...

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..The role of JNK mitogen-activated protein kinase activation may be limited in the pathogenesis of bronchial hyperresponsiveness after single allergen exposure...

..Glucocorticoids and theophylline may downregulate the inflammatory response by modulating HAT and HDAC activity, and nuclear factor-kappaB activation...

..This hypothesis raises the possibility that novel therapeutic approaches might unlock this corticosteroid resistance, leading to more effective anti-inflammatory treatments for COPD and other severe inflammatory diseases...

..In conclusion, we report here for the first time that posttranslational modification of GR by this novel nitrosteroid is associated with its enhanced anti-inflammatory activity...

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..In conclusion, we provide evidence that glucocorticoids are unable to repress the activity of NF-kappaB in renal epithelial cells in the presence of an intact stimulatory pathway...

..NO generated through NOS2 contributes to allergen-induced bronchial hyperresponsiveness but not to bronchial eosinophilia, indicating that these are independently expressed...

..Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis...

..The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids...

..The present data suggests that mometasone has opposite effects on apoptosis of human eosinophils and neutrophils at clinically relevant drug concentrations via an effect on glucocorticoid receptor...

..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...

..CONCLUSION: These data show that p38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and reestablishing the beneficial effects of glucocorticoids in patients with severe asthma...

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..Therefore, theophylline might restore steroid responsiveness in COPD patients...

..Encouraging data from animal models, primary cells and clinical studies in other diseases suggest that inhibitors of PI3K/Akt may prove to be useful novel therapies in the treatment of asthma and chronic obstructive pulmonary disease...

..Clearly this is an exciting new area of ongoing research with promising therapeutic potential...

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..Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-kappaB-mediated, but not GRE-mediated, gene expression...

..Our results suggest that IL-1beta-stimulated transcription of TGF-beta1 is temporally regulated by NF-kappaB and AP-1 and involves histone hyperacetylation at distinct promoter sites...

..Oxidative stress due to cigarette smoke may be an important factor in inducing glucocorticoid resistance in chronic obstructive pulmonary disease and may involve changes in histone acetylation/deacetylation balance...

..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...

..Genes identified in both studies play a functional role in the cytoskeleton, integrin signaling, and oncosuppression, themes that have been shown to be important in parvovirus infections...

..CONCLUSIONS: Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease...

..Together, our data confirm that GR nuclear translocation may underlie the complementary interactions between LABAs and corticosteroids, although the precise signal transduction mechanisms remain to be determined...