Chronic obstructive pulmonary disease (COPD) is emerging as a major leading cause of morbidity and mortality in the United States and other countries. Abnormal lung cell proliferation and apoptosis, as well as extracellular matrix degradation, can alter lung cell homeostasis and architecture, leading to the development and progression of COPD. Thus, elucidating the mechanisms regulating these abnormal lung cellular processes may advance our understanding of COPD and may enable us to devise better strategies for therapeutic intervention. The human genome encodes ~ 56 b-ZIP proteins that play key roles in regulating various cellular processes, including the maintenance of tissue homeostasis. Among the most prominent and well-studied b-ZIP proteins are the Jun (c-Jun, Jun-B, and Jun-D) and Fos (c-Fos, Fos-B, Fra-1, and Fra-2) families of transcription factors. Through homo- and heterodimerization, these b-ZIP proteins form a dimeric complex known as the activator protein 1 (AP-1). AP-1 has been found to display remarkable specificity and functional importance by differentially activating gene expression. However, the expression and activation patterns of the b-ZIP proteins during the development and progression of COPD remain enigmatic. In our preliminary studies, we found that, over time, genetic disruption of the c-Jun/AP-1 transcription factor in type II epithelial cells causes enlargement of the alveolar air spaces and lung inflammation, which are cardinal features of emphysema. Interestingly, an elevated level of Fra-1 expression has been reported in the lungs of cigarette smoke-exposed mice that have developed emphysema. We have recently shown that cigarette smoke, a major determinant of COPD, strongly stimulates Fra-1 expression in lung epithelial cells. Furthermore, we have demonstrated that overexpression of Fra-1 induces matrix metalloproteinase gene expression and a fibroblastic phenotype in type II epithelial cells. Fra-1 has also been shown to regulate transrepression of the elastin gene transcription that is promoted by growth factors secreted from by extracellular matrix in response to elastase activity. These studies performed in cell culture and animal models provide compelling preliminary evidence that AP-1 signaling plays a role in COPD. Based on these data, we now postulate that dysfunctional AP-1 (c-Jun and Fra-1)-regulated gene expression contributes to the development of COPD. To test this hypothesis, we will analyze the expression and activation pattern of c-Jun and Fra-1, as well as other members of the AP-1 family, in clinical biopsies (provided by the Lung Tissue Research Consortium, LTRC) of the lungs of nonsmokers, ex-smokers, and smokers with or without progressive emphysema. The results obtained will not only allow us to correlate AP-1 signaling with COPD severity but also provide a strong rationale for further targeting Jun and Fos family members using lung-specific targeted mouse models and experimental emphysema.
Various cellular processes, including proliferation, differentiation, metabolism, and stress responses, are deregulated in the lungs of COPD patients. The goal of the present study is to determine whether the expression and activation patterns of the AP-1 (Jun/Fos) family of transcription factors, which regulate above cellular processes, are altered during the development and progression of COPD and whether such changes are associated with a specific cell and molecular phenotype in COPD. These studies will to further define the roles of these proteins in COPD by utilizing lung-targeted mouse models and experimental emphysema and to develop new small molecule activators/inhibitors targeting the AP-1 pathway for therapeutic intervention.
