Journal Article

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

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

2015

Overview

IntroductionIdiopathic 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.MethodsS1P 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.ResultsS1PL 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.ConclusionThese studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.

• Publisher: BMJ Publishing Group LTD
• Subject: Aldehyde-Lyases - metabolism / Animals / Autophagy / Autophagy - physiology / Cell Differentiation - physiology / Consortia / Disease Models, Animal / Fibroblasts / Fibroblasts - metabolism / Health sciences / Humans / Immunohistochemistry / Inflammation / Kinases / Leukocytes, Mononuclear - metabolism / Lung - cytology / Lung - metabolism / Lungs / Mice / Pathogenesis / Phosphatase / Pulmonary fibrosis / Pulmonary Fibrosis - metabolism / Radiation / Signal Transduction - physiology / Smad Proteins - physiology / Smooth muscle / Transforming Growth Factor beta - physiology / Up-Regulation - physiology