ABSTRACT
There is an urgent need to develop effective treatments for chronic obstructive pulmonary disease (COPD). In striking contrast to the recent advances in understanding and treating asthma, COPD has received little attention, and there are few new drugs in development for this important disease. There are several possible reasons for the lack of drug development for this disease. COPD has been perceived as a disease of ‘‘untreatable’’ fixed airflow obstruction. Patients with COPD are usually treated with anti-asthma therapies, but these drugs are usually inappropriate in a disease with a strikingly different pathophysiology. Since in most patients COPD is the result of long-term heavy cigarette smoking, it is considered to be self-inflicted and not deserving of high medical expenditure. In addition, there has been little research in the molecular and cell biology of COPD to identify new therapeutic targets and there are no satisfactory animal models for early drug testing. Lastly, there are uncertainties about how to test new drugs for COPD, as this may require long-term studies in large numbers of patients and there is a lack of surrogate markers to monitor the short-term efficacy of new treatments. However, some progress is being made and several classes of drug are now in preclinical and clinical development (1-3). This is based on a better understanding of the pathophysiology of COPD, which has
944 Barnes
Figure 1 Targets for COPD therapy based on current understanding of the inflammatory mechanisms. Cigarette smoke (and other irritants) activate macrophages in the respiratory tract that release neutrophil chemotactic factors, including interleukin-8 (IL-8) and leukotriene B4 (LTB4). These cells then release proteases that break down connective tissue in the lung parenchyma, resulting in emphysema, and also stimulate mucus hypersecretion. These enzymes are normally counteracted by protease inhibitors, including α1-antitrypsin, secretory leukoprotease inhibitor (SLPI), and tissue inhibitor of matrix metalloproteinases (TIMP). Cytotoxic T cells (CD8) may also be involved in the inflammatory cascade.
