TGF-beta1 inhibits surfactant component expression and epithelial cell maturation in cultured human fetal lung

Am J Physiol. 1998 Nov;275(5):L950-60. doi: 10.1152/ajplung.1998.275.5.L950.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoproteins / biosynthesis
  • Apoproteins / genetics*
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology*
  • Fetus
  • Humans
  • Lung / cytology
  • Lung / drug effects
  • Lung / physiology*
  • Lung / ultrastructure
  • Proteolipids / biosynthesis
  • Proteolipids / genetics*
  • Pulmonary Surfactant-Associated Proteins*
  • Pulmonary Surfactants / biosynthesis
  • Pulmonary Surfactants / genetics*
  • RNA, Messenger / analysis
  • Recombinant Proteins / pharmacology
  • Transcription, Genetic* / drug effects
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta / physiology

Substances

  • Apoproteins
  • Proteolipids
  • Pulmonary Surfactant-Associated Proteins
  • Pulmonary Surfactants
  • RNA, Messenger
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • pulmonary surfactant apoprotein
  • Dexamethasone