COPD is highly prevalent disease, and is an important cause of disability and death in most countries. In the United States, it is estimated that over 14 million people suffer from this disease. The major etiological agent in COPD is cigarette smoke. Recent studies indicate that the lung epithelium is an active participant in the pathogenesis of this disease and plays a critical role in the lung response to cigarette smoke. Our laboratory has found that MMP-1 is expressed in epithelial cells of the lung from patients with emphysema and not in normal controls. In addition, transgenic animals that express MMP-1 in their lung develop progressive lung destruction over time with an increase in lung compliance consistent with emphysema. Through in vitro and in vivo studies, we have demonstrated that smoke exposure directly activates the MAP kinase pathway within the lung epithelium thus inducing expression of genes potentially involved in the pathogenesis of COPD. Through these studies, we have shown that smoke can directly induce MMP-1 expression within epithelial cells. This occurs through the activation of the MAP kinase pathway. In this application, we propose to further examine the role of the lung epithelium, collagenases, and the signaling cascade that induces collagenase expression in COPD. We are also expanding the expertise of my own laboratory by collaborations with Dr. Peter Pare and his group to explore genetics of COPD. We hypothesize that in COPD, one cause of smoke induced injury and persistent lung destruction is the induction of MMP expression by the activation of the MAP Kinase pathway within the epithelium of the lung. We will test this hypothesis in three specific aims: (1) Characterize the cigarette smoke responsive elements within the MMP-1 promoter;(2) Determine associations between polymorphisms in the MMP-1 promoter and susceptibility with COPD and COPD severity;and (3) Test the hypothesis that MAP kinase activation by cigarette smoke is a critical event in the activation of genes leading to tissue destruction and emphysema formation. It is essential that COPD research focus on improving our understanding of the specific cellular and biochemical injury induced by smoke within the lung. The proposed studies will provide insight into the role of smoke and MAP kinase signaling in airway injury, which occurs in COPD. The identification of transcription factors regulating protease expression in post smoke exposure will provide novel insight into the pathogenesis of COPD.
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