Peter J Barnes

..Nitrative stress is implicated in COPD pathogenesis, but PN has not been detected due to a short half-life (< 1 s) at physiologic condition. Instead, 3-nitrotyrosine has been measured as a footprint of PN release...

..Thus although there have been major advances in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are safe and effective...

..Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments...

..Improved immunotherapy approaches have the potential for disease modification, although prospects for a cure are currently remote...

..abstract:..

..The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response...

..Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy...

..However, addition of LABA and LTRA may be equal with respect to asthma exacerbations. However, more and longer studies are needed to better clarify the role of LTRAs and theophylline as add-on therapies...

..Our observations are the first to identify mechanisms of endothelium dependent dilations in precision cut lung slices and the potential for transverse hormonal communication between airways and vessels...

..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...

..Exhaled breath condensate (EBC) is a non-invasive method to assess airway inflammation and oxidative stress and may be useful in the assessment of childhood asthma...

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

..92, p<0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences...

....

..Many novel receptors, including orphan receptors, have now been identified as these may be future targets for developing novel therapies for asthma and chronic obstructive pulmonary disease...

..It is likely that modulators of signal transduction pathways may lead to the development of several novel anti-inflammatory treatments for asthma and COPD in the future...

..Better understanding of the molecular basis for the action of theophylline might lead to the development of novel drugs...

..It seems likely that pharmacology, rather than molecular genetics, will remain the main approach to the further improvement of treatment for asthma...

..This mechanism is also relevant to asthmatic patients who smoke, patients with severe asthma and cystic fibrosis, in whom oxidative stress is also increased...

..The therapeutic implications of these new findings are discussed...

..In the future, pulmonary biomarkers may be useful in predicting disease progression, indicating disease instability, and in predicting response to current therapies and novel therapies, many of which are now in development...

..Theophylline, by activating HDAC, may reverse this corticosteroid resistance. This research may lead to the development of novel anti-inflammatory approaches to manage severe inflammatory diseases...

..There is also a search for elastase inhibitors to prevent the development of emphysema and drugs that may even reverse the lung destruction...

..This inflammation, in marked contrast to asthma, appears to be resistant to corticosteroids, prompting a search for novel anti-inflammatory therapies that may prevent the relentless progression of the disease...

..More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies...

..Improvements in inhaled drug delivery will continue to be paramount in improving asthma management...

..There is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD...

..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...

..Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD...

..New anti-inflammatory therapies include corticosteroids and inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase and nuclear factor-kappaB. The prospects for a curative treatment are on the horizon...

..There is no doubt that the type of inhaler is just as important as the class of drug in the long-term management of asthma. Improvements in inhaled drug delivery will continue to be important in improving asthma management...

..HDACs may be inhibited directly by siRNA and in the future by small-molecule activators may be discovered through high output screening. These drugs may represent a novel approach to treating chronic inflammatory diseases...

..There are several novel therapeutic strategies targeted at macrophages...

..The identification of inflammatory mediators and understanding their interactions is important for the development of anti-inflammatory treatments for this important disease...

..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...

....

..Prospects for a cure are currently remote but might arise from the development of vaccines that target the aberrant immune function in asthma...

..Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment...

....

....

..In the future selective PI3Kdelta inhibitors and more direct activators of HDAC2 may be used to treat corticosteroid-resistant inflammatory diseases of the lung, including COPD, severe asthma and asthma in smokers...

....

..This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease)...

..In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanism of glucocorticoid resistance...

..In the future, alternative anti-inflammatory treatments will be needed for COPD or therapeutic strategies which reverse the molecular pathways that causes corticosteroid resistance...

..Improved immunotherapy approaches have the prospect of disease modification, although prospects for a cure are currently remote. The most promising therapeutic developments for asthma are discussed in this review...

..This might be achieved by theophylline-like drugs, phosphoinositide 3 kinase-delta inhibitors, more effective antioxidants and non-antibiotic macrolides...

..In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance...

..Corticosteroids are highly effective with a broad spectrum of anti-inflammatory effects, including epigenetic modulation of the inflammatory response and suppression of GATA3...

..This might be achieved by theophylline-like drugs, more effective antioxidants, and nonantibiotic macrolide agents...

..Accelerated aging may be associates in common to COPD and several comorbidities, prompting the development of antiaging molecules, such as sirtuin 1 agonists, which may also be effective in reducing the risk of lung cancer...

..It is also likely that several novel treatments that are developed as analgesics will also prove to be beneficial in the treatment of cough...

..Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD...

..There is now a strong scientific rationale for single inhaler therapy in asthma, but more research is now needed to better understand the mechanisms involved...

..Antioxidants, long-acting beta(2)-agonists, and activators of histone deacetylase may also be effective...

..This has important implications for the development of new therapies...

..Perhaps the most promising approach is reversal corticosteroid resistance through increasing HDAC2 activity. This may be achieved by theophylline-like drugs, more effective antioxidants and non-antibiotic macrolides...

..Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future...

..Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low concentrations of theophylline and curcumin, which act as HDAC activators...

....

..There are beneficial molecular interactions between β(2)AR and glucocorticoid-activated pathways. Understanding these signaling pathways may lead to even more effective therapies in the future...

....

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

..We investigated the effect of the corticosteroid fluticasone propionate on GATA-3 regulation in human T-lymphocytes in vitro and in vivo...

..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...

..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...

....

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

..The cells were not steroid insensitive because steroids inhibited GM-CSF release. Therefore, although these cells express iNOS under inflammatory conditions, they do not appear to be regulated directly by glucocorticosteroids...

..NO production is increased in patients with COPD, and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD...

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

..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...

..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...

..However, the clinical benefits from inhibiting mucus hypersecretion are still not certain, casting some doubts on this therapeutic approach...

..Asthmatic subjects have elevated Deltae degrees T. This may represent a novel, noninvasive means of measuring airway blood flow and inflammation in asthma...

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

..We conclude that impaired nuclear recruitment of HDAC2 could be an important mechanism of steroid resistance of the neutrophilic inflammation in exacerbations of asthma. Oxidative stress may contribute to decreased HDAC2 activity...

..Corticosteroids are likely to remain the mainstay of asthma therapy and new therapeutic strategies may reverse the corticosteroid insensitivity in COPD and severe asthma...

..However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis...

..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...

..These results suggest that theophylline has antiinflammatory properties that may be useful in the long-term treatment of COPD...

..CONCLUSIONS: Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations...

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

....

..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...

....

..Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids. This has been linked to a reduction of histone deacetylase-2 as a result of oxidative stress and is reversed by theophylline...

..We therefore suggest that IKK inhibitors may be of considerable benefit in inflammatory airways diseases, particularly in COPD or severe asthma, in which corticosteroids are ineffective...

....

..The pH of exhaled breath condensate (EBC) is a promising marker. Although pH has been measured in the EBC of adults with inflammatory airway diseases, no study has measured this in children...

..Based on these promising features, it is likely that tiotropium used alone or in combination with other bronchodilators will emerge as first-line maintenance treatment for patients with airway obstruction due to COPD...

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

..Taken together, the results presented here suggest that, whilst transcriptional processes predominantly regulate IL-5 release, the mechanism by which dexamethasone inhibits IL-5 is post-transcriptional...

..CONCLUSION: We conclude that the long-acting beta(2)-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma, but that there is no difference in efficacy between the two drugs...