Studies of development of organ systems other than the lung during fetal life has demonstrated importance of mesenchymal-epithelial interactions wither through release of soluble growth factors or through peptides in the interstitial matrix. Preliminary work on the lung also indicates a role for mesenchymal-epithelial interactions and that cellular activities may be temporarily and specially regulated. During branching morphogenesis cellular proliferation is important whereas in later gestation differentiation of airway epithelial cells into type Two cells which synthesize pulmonary surfactant becomes crucial. This application addresses two growth factors, transforming growth factor alpha (TGF-a) and hepatocyte growth factor (HGF), with emphasis on their effects on type II cells. These factors have been chosen because 1) production by fetal lung fibroblasts is gestational age dependent, 2) both factors may stimulate surfactant synthesis in fetal type II cells, 3) fetal type II cells have HGF receptors and 4) and HGF stimulates proliferation of both fetal and type II cells in primary culture. It is hypothesized that TGF-a and HGF regulate changes in the proliferation and differentiated function of alveolar epithelial cells during fetal development contributing to regulation of surfactant in the fetus and newborn. The four Specific Aims are 1) to define the ontogeny of TGF-a and HGF production in fetal lung fibroblasts and the developmental pattern of their receptors in Type II cells; 2) Isolate and partially sequence the principal isoform of TGF-a in fetal rat lung fibroblasts; 3) To isolate the fetal isoform of TGF-a and test effects on fetal type II cell function; 4) to examine the role of protein kinase C in effects of TGF-a by using inhibitors. These studies will define expression and function of the two growth factors during fetal lung development and contribute to our understanding of the regulation of this process.
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