Novel approaches and targets for treatment of chronic obstructive pulmonary disease.

There is a driving need to develop new and effective treatments for COPD. Bronchodilators are now the mainstay of symptomatic therapy and a new long-acting anticholinergic bronchodilator, tiotropium bromide, is now in advanced clinical trials as a once daily dry powder inhaler. Several inflammatory mediators are involved in the chronic neutrophilic inflammation that typifies COPD, including leukotriene B(4) and interleukin 8, for which specific receptor antagonists have been developed. Since the inflammatory process in COPD is essentially steroid resistant, new antiinflammatory treatments are needed. Drugs that may be effective include phosphodiesterase 4 inhibitors, NF-kappaB inhibitors, and interleukin 10. Inhibition of proteases is another approach and inhibitors of neutrophil elastase, cathepsins, and matrix metalloproteases are now in clinical development. Supply of endogenous antiproteases, such as alpha(1)-antitrypsin and secretory leukocyte protease inhibitors as recombinant proteins or by gene transfer, is also being explored. In future drugs that may stimulate alveolar repair might be developed, including retinoid receptor agonists and hepatic growth factor. Future directions will include earlier detection of disease, gene profiling to identify which smokers are at risk of COPD, and the development of noninvasive surrogate markers to monitor disease activity in order to monitor new therapies. Identification of genes that confer a risk for COPD in smokers may identify novel targets for drug development. Barnes PJ. Novel approaches and targets for treatment of chronic obstructive pulmonary disease.