Testing drugs in animal models of cigarette smoke-induced chronic obstructive pulmonary disease.

Animal models of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) provide potentially useful ways to test drug therapies, either by direct administration of the treatment of interest, or by use of genetically modified animals that mimic the actions of the drug of interest. Evaluation of the potential effects of a drug in animal models requires a long-term (generally 6-mo) smoke exposure to produce/prevent lesions because acute models do not completely predict chronic events. There are now more than 30 chronic studies in the literature which, in aggregate, show that antiproteolytic therapies, antiinflammatory therapies, and antioxidant therapies substantially or completely prevent emphysema, small airway remodeling, and pulmonary hypertension in laboratory animals. However, the few corresponding trials in humans (anti-TNF-alpha therapy, PDE4 inhibitors) have produced only minor improvements or failed to prevent disease progression. New data from our laboratory indicates that, at least for murine emphysema, the development of disease goes through different phases, with early repair and late failure to repair smoke-induced damage. These observations suggest that the potential effects of drug treatment in humans may vary depending on the stage of the disease and that treatment may be more effective in relatively early disease. An additional complicating factor is that interventions that ameliorate emphysema may or may not prevent small airway remodeling and/or pulmonary hypertension, suggesting that different therapeutic approaches may be needed for the various different anatomic lesions of COPD.