TGF-BETA-1 INHIBITS SURFACTANT COMPONENT EXPRESSION AND EPITHELIAL-CELL MATURATION IN CULTURED HUMAN FETAL LUNG

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cy tokine shown to play a critical role in organ morphogenesis, developme nt, growth regulation, cellular differentiation, gene expression, and tissue remodeling after injury. We examined the effect of exogenously administered TGF-beta 1 on the expression of surfactant proteins (SPs) and Lipids, fatty acid synthetase, and ultrastructural morphology in human fetal lung cultured for 5 days with and without dexamethasone (1 0 nM). Expression of the type II cell-specific marker surfactant propr otein C (proSP-C), studied by [S-35]Met incorporation and immunoprecip itation, increased sevenfold with dexamethasone treatment. TGF-beta 1 (0.1-100 ng/ml) in the presence of dexamethasone inhibited 21-kDa proS P-C expression in a dose-dependent manner (maximal inhibition 31% of c ontrol level at 100 ng/ml). There was no change in [S-35]Met incorpora tion into total protein in any of the treatment groups vs. the control group. In immunoblotting experiments, TGF-beta 1 blocked culture-indu ced accumulation of SP-A and SP-B. Under the same conditions, TGF-beta 1 reduced mRNA content for SP-A, SP-B, and SP-C to 20, 38, and 41%, r espectively, of matched control groups but did not affect levels of be ta-actin mRNA. SP transcription rates after 24 h of exposure to TGF-be ta 1 were reduced to a similar extent (20-50% of control level). In bo th control and dexamethasone-treated explants, TGF-beta 1 (10 ng/ml) a lso decreased fatty acid synthetase mRNA, protein, and enzyme activity and the rate of [H-3]choline incorporation into phosphatidylcholine. By electron microscopy, well-differentiated type II cells Lining poten tial air spaces were present in explants cultured with dexamethasone, whereas exposure to TGF-beta 1 with or without dexamethasone resulted in epithelial cells lacking lamellar bodies. We conclude that exogenou s TGF-beta 1 disrupts culture-induced maturation of fetal lung epithel ial cells and inhibits expression of surfactant components through eff ects on gene transcription.