Apoptosis and defective repair in COPD

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DESCRIPTION (provided by applicant): The central thesis of this project is that normal alveolar cell homeostasis is dysregulated in COPD. Increased apoptosis of alveolar cells, coupled with the defective ability to recognize, clear and replace these cells, is suggested to lead to loss of alveolar structure and emphysema. Recognition of apoptotic cells is a highly regulated process that results not only in their removal but also in generation of anti-inflammatory mediators, anti-proteases and growth factors, all of which are decreased in COPD. We further suggest that these processes involve activation of the Wnt/catenin pathways - also presumptively altered in COPD. Here we will compare these putative defective responses in smokers and COPD patients to non-smoking controls. In addition, evidence of defective cell replication and ¿-catenin responses will be similarly examined and correlated with the altered response to, and clearance of, apoptotic cells. Statins have been shown to enhance the removal of apoptotic cells, to prevent cigarette smoke-induced emphysema in rodents, and in recent epidemiologic studies, to improve clinical outcomes in COPD patients. Accordingly, lovastatin will be examined in pilot intervention studies with COPD patients for its ability to reverse the defects in apoptotic cell clearance, enhance suppression of inflammatory mediators, proteases, and restore growth factors and ¿-catenin pathways. Since statins are also known to have direct anti-inflammatory and immunomodulatory effects that go beyond their ability to enhance apoptotic cell removal, lovastatin-treated patients will also be followed for possible reduction in the inflammatory responses. Preliminary evidence for defects in apoptotic cell uptake by circulating mononuclear phagocytes in COPD will be followed to address systemic, and perhaps fundamental, functional abnormalities, effects of statins, and also, potentially, to develop blood-based biomarkers. We suggest that these studies and intervention will show reversal of processes leading to disease progression and even, possibly evidence of enhanced lung repair. Chronic Obstructive Lung Disease (COPD) is the 4th leading cause of death and disability in the United States, and is generally associated with current or former cigarette smoking. This proposal will explore the hypothesis that in COPD, abnormal responses of the lung to damaged cells leads to defective tissue repair after injury and that this then contributes to the structural abnormalities seen in this condition. The studies will involve in vitro and animal systems as well as samples from COPD patients, smokers without COPD and normal non- smokers. We will also perform an interventional study in COPD patients with lovastatin, which is known to reverse the defective response to damaged cells in vitro and in mice exposed to cigarette smoke, and we propose, may also reverse the abnormal effects in our patients.