Role of endogenous TGF-β in glucocorticoid-induced lung type II cell differentiation

Abstract

In the fetal lung, endogenous transforming growth factor (TGF)-β inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-β inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-β. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-β, which was activated in part by αVβ6-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-β1 and -β2 transcripts and TGF-β bioactivity in culture medium. To examine the effects of decreased TGF-β in the absence of glucocorticoid, cells were treated with antibodies to TGF-β and its receptors. By real-time RT-PCR, antibody blockade of TGF-β reduced serpine1, a TGF-β-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-β antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-β suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-β gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-β and glucocorticoids.

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

“…In accordance with previous studies (see Table 4 for literature overview), fetal rabbits after TO displayed transcriptional changes compatible with accelerated alveolar type II cell transdifferentiation. Among factors regulating this process, transcription thyroid factor-1 decreased after TO in nitrofen-induced CDH lungs (9), but increased after TGF-␤ blockade in lung epithelial cells (38). Consistent with in vitro data (67), these findings imply a role for TGF-␤ in TO-mediated epithelial transdifferentiation.…”

Biosynthesis of phosphatidylcholine by human lysophosphatidylcholine acyltransferase 1

“…Third, hLPCAT1 is highly expressed in the human lung. In addition to these fi ndings, hLPCAT1 mRNA (which was called AYTL2 in the report) was shown to be upregulated during in vitro differentiation of alveolar type II cells ( 30 ). Our preliminary data suggest that hLPCAT1 exhibits substrate specifi city for palmitoyl-CoA (T. Harayama, H. Shindou, and T. Shimizu, unpublished observations).…”

Unique Tracheal Fluid MicroRNA Signature Predicts Response to FETO in Patients With Congenital Diaphragmatic Hernia

“…During fetal lung development, endogenous TGF-β blocks hormone-induced type II epithelial cell differentiation. 41 Decreased TGF-β activity in late stages of lung development might explain why human cases of CDH display normal surfactant maturation. 42,43 In addition, exogenous surfactant has been demonstrated to be of no benefit in the treatment of pulmonary hypoplasia associated with CDH.…”