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

Long Shuang Huang, Evgeny V. Berdyshev, John T. Tran, Lishi Xie, Jiwang Chen, David L. Ebenezer, Biji Mathew, Irina Gorshkova, Wei Zhang, Sekhar P. Reddy, Anantha Harijith, Gang Wang, Carol Feghali-Bostwick, Imre Noth, Shwu Fan Ma, Tong Zhou, Wenli Ma, Joe G.N. Garcia, Viswanathan Natarajan

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Introduction: 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. Methods: 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. Results: 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 beclin1. 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. Conclusion: These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.

Original languageEnglish (US)
Pages (from-to)1138-1148
Number of pages11
JournalThorax
Volume70
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Shuang Huang, L., Berdyshev, E. V., Tran, J. T., Xie, L., Chen, J., Ebenezer, D. L., Mathew, B., Gorshkova, I., Zhang, W., Reddy, S. P., Harijith, A., Wang, G., Feghali-Bostwick, C., Noth, I., Ma, S. F., Zhou, T., Ma, W., Garcia, J. G. N., & Natarajan, V. (2015). Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: Role of S1P signalling and autophagy. Thorax, 70(12), 1138-1148. https://doi.org/10.1136/thoraxjnl-2014-206684