The goal is to investigate the regulatory role which extracellular matrix (ECM) exerts on type II pneumocytes. The extracellular components of the lung have long been known to influence the physical/mechanical properties of the tissue and thereby to play an important role in the function of normal and diseased tissue. alterations in the content and/or organization of connective tissue elements are involved in pulmonary fibrosis and emphysema, both of which are of extensive clinical significance. Recent reports of the effects of ECM on cellular proliferation and differentiation make it clear that ECM constituents cannot be regarded as an inert scaffold, but that they exert significant effects at the metabolic level. The overall goal of the proposed research is thus to investigate the hypothesis that the ECM of the lung exerts a regulatory effect on differentiated metabolism and function of type II pulmonary epithelial cells. The approach involves definition of the effects of biologically significant ECMs on type II cell morphology, as well as on retention of a typical metabolic profile. Specific metabolic steps at which these effects are exerted will be identified and these changes will be attributed to specific ECM components and/or characteristics. ECMs to be investigated range from well-defined materials, including collagens, laminin and fibronectin, to biological matrices of complex composition, including """"""""biomatrix"""""""" isolated from whole lung and """"""""matrix gel"""""""" elaborated by an EHS-tumor. Parameters to be monitored, which appear to provide an index of differentiated type II cell function, include cell viability, morphology, size and shape; synthesis and secretion of phospholipids and proteins associated with surfactant production; the presence of typical cytoskeletal and/or membrane characteristics, including expression of specific keratins and activit;y of Beta-adrenergic receptor-ligand interations; and the quantity, activity ratio and isozyme pattern of the cyclicAMP-dependent protein kinase system. Further investigations will extend these baseline observations to examine the effects of paraquat-induced oxidant damage on ECM function and on the interaction of type II cells with their substratum. Together, these experiments will define the biochemical mechanisms by which ECM components influence maintenance expression and physiological control of differentiated metabolic function of type II cells, as well as how these influences may be affected by oxidant damage.
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