LUNG ALVEOLAR EPITHELIAL CELL DIFFERENTIATION

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Mesenchymal-epithelial interactions are known to be required for the morphogenesis of the fetal lung. Mesenchymal-epithelial interactions may be mediated, in part, by the extracellular matrix. We hypothesize that changes in the composition and structure of the extracellular matrix precede, or else are concomitant with the differentiation of fetal lung alveolar epithelial cells. Recently, transforming growth factor beta (TGFbeta), a growth factor that is known to regulate extracellular matrix composition, has been shown to inhibit the expression of SP-A, a surfactant-associated protein that is synthesized in differentiated type II cells. Conversely, epidermal growth factor, (EGF), another growth factor known to regulate extracellular matrix production, increases the expression of SP-A and stimulates lung maturation. We propose to localize and evaluate changes in the levels of TGFbeta and EGF, or its homologue, TGFalpha, during the course of fetal rabbit lung maturation in vivo using morphological and molecular biology techniques. We will characterize the effects of these growth factors on the structure and composition of the extracellular matrix in rabbit differentiation in the explants. We have shown previously that fetal lung fibronectin concentrations increase at the time of alveolar epithelial cell differentiation. We propose to extend these studies by determining the effects of TGFbeta and EGF on the levels of fibronectin mRNA as well as on the levels of mRNA for the fibronectin receptor. Finally, we propose to evaluate the effects of extracellular of mRNA for the fibronectin receptor. Finally, we propose to evaluate the effects of extracellular matrix components on the maintenance of differentiation in purified type II cells maintained in monolayer culture. We will relate extracellular matrix- induced changes in the cytoskeleton and cell shape to the degree of type II cell differentiation in vitro, in particular with respect to the expression of SP-A. Thus, we will document the distribution, levels of mRNA, and actions of two growth factors TGFbeta and EGF, in fetal lung tissue. We hypothesize that one of the mechanisms by which these growth factors act to influence lung maturation involves the regulation of the composition and structure of he extracellular matrix. Therefore, we will document the effects of these growth factor on the metabolism of extracellular matrix components. The results of our studies will increase knowledge concerning the role of the extracellular matrix in the regulation of cell differentiation a well as the role of growth factors in the regulation of fetal lung development.