Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy.

TitleSphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy.
Publication TypeJournal Article
Year of Publication2015
AuthorsHuang LShuang, Berdyshev EV, Tran JT, Xie L, Chen J, Ebenezer DL, Mathew B, Gorshkova I, Zhang W, Reddy SP, Harijith A, Wang G, Feghali-Bostwick C, Noth I, Ma S-F, Zhou T, Ma W, Garcia JGN, Natarajan V
JournalThorax
Volume70
Issue12
Pagination1138-48
Date Published2015 Dec
ISSN Number1468-3296
KeywordsAldehyde-Lyases, Animals, Autophagy, Cell Differentiation, Disease Models, Animal, Fibroblasts, Humans, Immunohistochemistry, Leukocytes, Mononuclear, Lung, Mice, Pulmonary Fibrosis, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Up-Regulation
Abstract

<p><b>INTRODUCTION: </b>Idiopathic pulmonary fibrosis (IPF) is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate (S1P) signalling plays a critical role in pulmonary fibrosis.</p><p><b>METHODS: </b>S1P lyase (S1PL) expression in peripheral blood mononuclear cells (PBMCs) was correlated with pulmonary functions and overall survival; used a murine model to check the role of S1PL on the fibrogenesis and a cell culture system to study the effect of S1PL expression on transforming growth factor (TGF)-β- and S1P-induced fibroblast differentiation.</p><p><b>RESULTS: </b>S1PL expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. TGF-β increased the expression of S1PL in human lung fibroblasts via activation and binding of Smad3 transcription factor to Sgpl1 promoter. Overexpression of S1PL attenuated TGF-β-induced and S1P-induced differentiation of human lung fibroblasts through regulation of the expression of LC3 and beclin 1. Knockdown of S1PL (Sgpl1(+/-)) in mice augmented bleomycin-induced pulmonary fibrosis, and patients with IPF reduced Sgpl1 mRNA expression in PBMCs exhibited higher severity of fibrosis and lower survival rate.</p><p><b>CONCLUSION: </b>These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.</p>

DOI10.1136/thoraxjnl-2014-206684
Alternate JournalThorax
PubMed ID26286721
Grant ListP01 HL98050 / HL / NHLBI NIH HHS / United States