Macrophages participate in both the debridement and reparative phases of the self-resolving inflammatory response. During the debridement phase, these cells synthesize and secrete a number of inflammatory mediators including hydrolytic enzymes that collectively degrade the connective tissue matrix, while in the repair phase, macrophages secrete growth factors and cytokines that stimulate the proliferation of mesenchymal and epithelial cells, and influence the extent to which these latter cells deposit elements of the new connective tissue matrix. How these divergent macrophage activities are regulated is largely unknown. Based on our own preliminary data and other indications in the literature, we hypothesize that these discrete macrophage activities are manifested through the sequential expression of two distinct macrophage """"""""phenotypes"""""""": a """"""""degradative"""""""" phenotype, defined by the increased synthesis of lysosomal enzymes such as beta-glucuronidase, and a putative """"""""reparative"""""""" phenotype, defined by an increased level of expression of fibrogenic growth factors such as IGF-1, IL-1beta, fibronectin and TGFbeta. The objectives of this proposal are threefold: Firstly, to investigate the mechanisms that control the expression of the """"""""degradative"""""""" macrophage phenotype and to define the mechanism of induction of this state by PDGF. Secondly, to determine the mechanism leading to the cessation of expression of the """"""""degradative"""""""" state and the proposed ensuing induction of expression of the """"""""reparative"""""""" state. Thirdly, we propose to determine the level of expression of macrophage genes in healthy individuals, and patients with interstitial lung diseases (e.g. interstitial pulmonary fibrosis) or with a predisposition to develop this disorder (e.g. progressive systemic sclerosis). Alveolar macrophages will be analyzed for the expression of multiple phenotype associated genes (including PDGF-B, IGF-1, IL-8, TNFalpha, complement Bf and fibronectin) using a quantitative polymerase chain reaction assay. In addition, we propose to begin to address the question of the functions of the interstitial macrophage in the pathology of interstitial lung diseases. Collectively, these investigations are expected to shed new light onto the mechanism(s) of macrophage involvement in tissue degradation and repair especially in the context of lung diseases in man.
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