Strain-induced fetal type II epithelial cell differentiation is mediated via cAMP-PKA-dependent signaling pathway.
Publication/Presentation Date
10-1-2006
Abstract
The signaling pathways by which mechanical forces modulate fetal lung development remain largely unknown. In the present study, we tested the hypothesis that strain-induced fetal type II cell differentiation is mediated via the cAMP signaling pathway. Freshly isolated E19 fetal type II epithelial cells were cultured on collagen-coated silastic membranes and exposed to mechanical strain for varying intervals, to simulate mechanical forces during lung development. Unstretched samples were used as controls. Mechanical strain activated heterotrimeric G-protein alpha(s) subunit, cAMP, and the transcription factor cAMP response element binding protein (CREB). Incubation of E19 cells with the PKA inhibitor H-89 significantly decreased strain-induced CREB phosphorylation. Moreover, adenylate cyclase 5 and CREB genes were also mechanically induced. In contrast, components of the PKA-independent (Epac) pathway, including Rap-1 or B-Raf, were not phosphorylated by strain. The addition of forskolin or dibutyryl cAMP to unstretched E19 monolayers markedly upregulated expression of the type II cell differentiation marker surfactant protein C, whereas the Epac agonist 8-pCPT-2'-O-Me-cAMP had no effect. Furthermore, incubation of E19 cells with the PKA inhibitor Rp-2'-O-monobutyryladenosine 3',5'-cyclic monophosphorothioate or transient transfection with plasmid DNA containing a PKA inhibitor expression vector significantly decreased strain-induced surfactant protein C mRNA expression. In conclusion, these studies indicate that the cAMP-PKA-dependent signaling pathway is activated by force in fetal type II cells and participates in strain-induced fetal type II cell differentiation.
Volume
291
Issue
4
First Page
820
Last Page
827
ISSN
1040-0605
Published In/Presented At
Wang, Y., Maciejewski, B. S., Lee, N., Silbert, O., McKnight, N. L., Frangos, J. A., & Sanchez-Esteban, J. (2006). Strain-induced fetal type II epithelial cell differentiation is mediated via cAMP-PKA-dependent signaling pathway. American journal of physiology. Lung cellular and molecular physiology, 291(4), L820–L827. https://doi.org/10.1152/ajplung.00068.2006
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
16751225
Department(s)
Department of Pediatrics
Document Type
Article