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Am J Physiol Lung Cell Mol Physiol 275: L950-L960, 1998;
1040-0605/98 $5.00
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Vol. 275, Issue 5, L950-L960, November 1998

TGF-beta 1 inhibits surfactant component expression and epithelial cell maturation in cultured human fetal lung

Michael F. Beers1, Kola O. Solarin2, Susan H. Guttentag3, Joel Rosenbloom4, Annapurna Kormilli3, Linda W. Gonzales3, and Philip L. Ballard3

1 Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine; 3 Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia; 4 Department of Anatomy and Histology, University of Pennsylvania School of Dental Medicine, Philadelphia 19104; and 2 Division of Neonatology, Department of Pediatrics, Allegheny University School of Medicine, Philadelphia, Pennsylvania 19134

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine shown to play a critical role in organ morphogenesis, development, 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 (10 nM). Expression of the type II cell-specific marker surfactant proprotein C (proSP-C), studied by [35S]Met incorporation and immunoprecipitation, increased sevenfold with dexamethasone treatment. TGF-beta 1 (0.1-100 ng/ml) in the presence of dexamethasone inhibited 21-kDa proSP-C expression in a dose-dependent manner (maximal inhibition 31% of control level at 100 ng/ml). There was no change in [35S]Met incorporation into total protein in any of the treatment groups vs. the control group. In immunoblotting experiments, TGF-beta 1 blocked culture-induced 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%, respectively, of matched control groups but did not affect levels of beta -actin mRNA. SP transcription rates after 24 h of exposure to TGF-beta 1 were reduced to a similar extent (20-50% of control level). In both control and dexamethasone-treated explants, TGF-beta 1 (10 ng/ml) also decreased fatty acid synthetase mRNA, protein, and enzyme activity and the rate of [3H]choline incorporation into phosphatidylcholine. By electron microscopy, well-differentiated type II cells lining potential 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 exogenous TGF-beta 1 disrupts culture-induced maturation of fetal lung epithelial cells and inhibits expression of surfactant components through effects on gene transcription.

transforming growth factor-beta 1; human fetal lung explants; surfactant proteins; fatty acid synthetase; dexamethasone


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