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

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 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.

CONCLUSION:

These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.

• Authors: 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
• Journal: Thorax (Thorax) Vol. 70 Issue 12 Pg. 1138-48 (Dec 2015) ISSN: 1468-3296 [Electronic] England
• PMID: 26286721 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Chemical References

• Smad Proteins
• Transforming Growth Factor beta
• Aldehyde-Lyases
• sphingosine 1-phosphate lyase (aldolase)

Topics

• Aldehyde-Lyases (metabolism)
• Animals
• Autophagy (physiology)
• Cell Differentiation (physiology)
• Disease Models, Animal
• Fibroblasts (metabolism)
• Humans
• Immunohistochemistry
• Leukocytes, Mononuclear (metabolism)
• Lung (cytology, metabolism)
• Mice
• Pulmonary Fibrosis (metabolism)
• Signal Transduction (physiology)
• Smad Proteins (physiology)
• Transforming Growth Factor beta (physiology)
• Up-Regulation (physiology)