Interstitial fibrosis can occur in response in injury or inflammation from a variety of causes. Many diverse mechanisms provoke tissue remodeling in an attempt to repair damage from infection, trauma or disease processes. The end result is a distortion of the normal architecture of the lung, with progressive impairment of gas exchange due to inappropriate and disordered deposition of connective tissue within the interstitium. The interstitial fibroblast synthesizes the bulk of the structural matrix within which lung parenchymal tissue is organized, and it is ultimately responsible for repair of damaged tissue. Thus, understanding of mechanisms that control synthetic and replicative functions of the fibroblast is paramount to unraveling mechanism of fibrosis. Our proposal focuses on the role of the extracellular matrix in control of replication, gene expression, protein synthesis, ligand binding and procoagulant activities of human lung fibroblasts. We will culture fibroblasts from normal adult lung tissue and fibrotic lung tissue to determine how the matrix influences pathogenesis of fibrosis. One of our hypotheses is that expression signals for synthesis of matrix components, procoagulant activity or enzyme activities originate within the extracellular matrix, itself. When fibroblasts migrate into an area of inflammation, possibly in response to chemotactic signals, contact with an altered matrix may subvert the normal repair process to development of a fibrotic lesion. A second hypothesis is that fibroblasts altered in vivo or injured in vitro form an altered matrix that enhances progression of the lesion. We will determine if fibrotic or injured fibroblasts secrete abnormal quantities or altered matrix proteins. We will compare the response of normal and fibrotic cells to various ligands to determine if stimulated mitogenesis plays a role. Thrombin and structually related coagulation proteins are of particular interest as fibrin appears early in the lesion. We will examine expression of the genes responsible for synthesis of collagens, tropoelastin, and fibronectin and for expression of fibronectin receptors. Each of these products will be analyzed at synthetic, transcriptional levels with sensitive in vitro techniques. These studies should help to unravel some of the cellular and molecular mechanisms relevant to the pathogenesis of pulmonary fibrosis.
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