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Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-a.Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kB and phosphoinositide-3 kinase-c. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B 4 antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema.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.

Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), a chronic inflammatory disease of the airway. The increased expression of inflammatory proteins results from enhanced gene transcription, as these mediators are induced in a cell‐specific manner. Changes in transcription depend on chromatin remodeling and the relative activities of histone acetyl‐transferases (HATs) and histone deacetylases (HDACs). We have shown that cigarette smoke reduces the expression of HDAC2 expression and HDAC activity in biopsies and alveolar macrophages. Cigarette smoke also enhanced IL‐1β–induced expression of tumor necrosis factor α (TNF‐α) by alveolar macrophages. TNF‐α release was enhanced by the HDAC inhibitor Trichostatin A and correlated significantly with HDAC activity. In addition, we show that glucocorticoid‐responsiveness is reduced in these cells and correlates with HDAC activity. Using a macrophage cell line, we show that hydrogen peroxide mimics cigarette smoke effects on HDAC activity and markedly attenuates dexamethasone inhibition of cytokine release. These results offer the first evidence for a suppressive effect of cigarette smoke on histone acetylation status. Reduced HDAC expression may account for the enhanced expression of inflammatory mediators such as GM‐CSF, IL‐8 and TNF‐α by cigarette smoke seen in lavage samples of smokers and patients with COPD. In addition, this mechanism may account for the reduced effectiveness of glucocorticoids in COPD.

The effect of a single oral dose (800 mg) of zileuton (A-64077), a specific 5-lipoxygenase inhibitor, on the early and late airway responses to inhaled allergen was studied in a randomised, double blind, placebo controlled, and crossover trial in nine subjects with atopic asthma. Leukotriene generation was also assessed in vivo by measuring urinary leukotriene (LT) E4 excretion, and ex vivo by measuring calcium ionophore stimulated whole blood LTB4 production. Zileuton almost completely inhibited ex vivo LTB4 production but reduced urinary excretion of LTE4 by only about half. There was a trend for the early asthmatic response to be less on the day of zileuton treatment, but this did not reach statistical significance (p = 0 08). The zileuton induced reduction in maximum fall in FEVy in the early asthmatic response was, however, significantly related to the reduction in urinary LTE4 excretion (r = 0 8), but not to the reduction in LTB4 generation ex vivo. There was no significant change in the allergen induced late asthmatic response, or in the increase in airway responsiveness to methacholine following antigen. The results provide some support for the hypothesis that the cysteinyl leukotrienes have a role in the allergen induced early asthmatic response. More complete in vivo inhibition of 5-lipoxygenase may be needed to produce a significant reduction in airway response to allergen challenge.