The extracellular components of tissues, including the lung, have long been known to govern their physical-mechanical properties. Alterations in the content and/or organization of connective tissue elements is involved in both emphysema and pulmonary fibrosis. Recent reports of the influence of components of the matrix on cellular proliferations and differentiation have made it clear that the extracellular matrix, including collagens, glycosaminoglycans, and glycoproteins such as laminin and fibronectin, cannot be regarded as an inert scaffold. The goal of this project is to establish the metabolic consequences of Type II cell interaction with normal and oxidant-damaged extracellular matrix in a primary cell culture model. Type II cell proliferation is a significant component of pulmonary response to oxidant-induced damage, but the consequences of doubling the number of Type II cells in the lung and factors eliciting this proliferation are not known, nor are the metabolic responses of Type II cells to normal or damaged matrix understood. This project will investigate the responses of Type II granular pneumocytes in primary culture to a range of chemically-defined and biologically elaborated extracellular materials. Materials to be examined are collagen (Type I vs. Type IV) in different physical forms, laminin, fibronectin, extracellular matrix produced by fibroblasts and by endothelial cells and """"""""biomatrix"""""""" isolated from whole lungs. Furthermore, the effect on Type II cell function of damage to matrix components and to matrix-producing cells by the oxidant paraquat will be examined. Type II functions to be monitored are a) synthesis and secretion of surfactant-associated proteins. Because pathways of protein metabolism are well defined, detailed analysis of the effects of environmental factors on specific steps of the process is possible, b) phosphotidylcholine secretion and its responsiveness to Beta-adrenergic agents, and c) activities of phosphatidic acid phosphohydrolase, cholinephosphate cytidylyl transferase, and non-specific esterases, all of which have been associated with the functional maturation of Type II cells. The mechanism by which Type II cell interaction with the extracellular environment modulates metabolism of surfactant-associated proteins will be explored in depth.
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