TGF-β1 is associated with pulmonary fibrosis in various lung injury models and with development of chronic lung disease of prematurity. We examined the effect of exogenously administered TGF-β1 on surfactant protein (SP) expression and lung morphology in a cultured human fetal lung model. Explants prepared from 19-24 wk gestation lungs were cultured for 5 d with or without dexamethasone (dex, 10 nM), TGF, or dex and TGF (added on day 1, 3 or 4). To study synthesis of SP-C, explants cultured with dex were labeled on day 5 of culture with 35S-met for 4h and immunoprecipitated with anti-NPROSP-C antiserum. Dex alone increased SP-C21 expression by 6.8±0.8-fold compared to untreated control. TGF induced a dose and time dependent inhibition of SP-C21 expression with maximal inhibition after 5 d at 100 ng/ml (31±10% of 5 d control) and a Ki of ≈30 ng/ml. There was no change in 35S-met incorporation into total protein in any of the treatment groups vs controls. ELISA analysis of samples cultured for 5 d in TGF revealed a dose dependent inhibition of SP-A protein accumulation with 53% inhibition occurring at 10 ng/ml and a Ki of ≈1 ng/ml. Commensurate with the inhibition of protein content, TGF (100 ng/ml) decreased mRNA content to 17%, 39% and 23% of control for SP-A, SP-B and SP-C, respectively. Transcription rates were similarly reduced vs control to 28% for SP-A, 7% for SP-B and 46% for SP-C. Light microscopy of tissue treated for 5 d with TGF (100 ng/ml) plus dex revealed markedly increased interstitial deposition of extracellular matrix compared to dex alone. We conclude that TGF-β1 disrupts culture- and dex-induced maturation of fetal lung epithelial cells by a mechanism involving transcriptional down-regulation of SP gene expression. We speculate that excessive TGF-β1 contributes to the pathogenesis of chronic lung disease of prematurity in part through modulation of epithelial cell function.
NIH P50HL56401
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Solarin, K., Ballard, P., Gonzales, L. et al. TGF-β1 Modulates Epithelial Cell Differentiation in Cultured Human Fetal Lung. • 300. Pediatr Res 41 (Suppl 4), 52 (1997). https://doi.org/10.1203/00006450-199704001-00320
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DOI: https://doi.org/10.1203/00006450-199704001-00320