title: TGF-beta1 inhibits surfactant component expression and epithelial cell maturation in cultured human fetal lung.
abstract: Transforming growth factor-beta1 (TGF-beta1) 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-beta1 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-beta1 (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-beta1 blocked culture-induced accumulation of SP-A and SP-B. Under the same conditions, TGF-beta1 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-beta1 were reduced to a similar extent (20-50% of control level). In both control and dexamethasone-treated explants, TGF-beta1 (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-beta1 with or without dexamethasone resulted in epithelial cells lacking lamellar bodies. We conclude that exogenous TGF-beta1 disrupts culture-induced maturation of fetal lung epithelial cells and inhibits expression of surfactant components through effects on gene transcription.
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Department of Pediatrics, Allegheny University School of Medicine, Philadelphia, Pennsylvania 19134, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Beers
authors.forename: K O
authors.initials: KO
authors.lastname: Solarin
authors.forename: S H
authors.initials: SH
authors.lastname: Guttentag
authors.forename: J
authors.initials: J
authors.lastname: Rosenbloom
authors.forename: A
authors.initials: A
authors.lastname: Kormilli
authors.forename: L W
authors.initials: LW
authors.lastname: Gonzales
authors.forename: P L
authors.initials: PL
authors.lastname: Ballard
mesh_terms: D001059:Apoproteins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005333:Fetus; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D011510:Proteolipids / Q000096:biosynthesis / Q000235:genetics*; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology
chemical_list: D001059:Apoproteins; D011510:Proteolipids; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C046616:pulmonary surfactant apoprotein; D003907:Dexamethasone