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Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy
  1. Long Shuang Huang1,
  2. Evgeny V Berdyshev2,
  3. John T Tran3,
  4. Lishi Xie4,
  5. Jiwang Chen2,
  6. David L Ebenezer5,
  7. Biji Mathew2,
  8. Irina Gorshkova2,
  9. Wei Zhang1,6,
  10. Sekhar P Reddy7,
  11. Anantha Harijith7,
  12. Gang Wang8,
  13. Carol Feghali-Bostwick9,
  14. Imre Noth10,
  15. Shwu-Fan Ma10,
  16. Tong Zhou11,
  17. Wenli Ma11,
  18. Joe G N Garcia11,
  19. Viswanathan Natarajan1,2
  1. 1Department of Pharmacology, The University of Illinois, Chicago, Illinois, USA
  2. 2Department of Medicine,The University of Illinois, Chicago, Illinois, USA
  3. 3Department of Biology, The University of Illinois, Chicago, Illinois, USA
  4. 4Department of Urology, The University of Illinois, Chicago, Illinois, USA
  5. 5Department of Biochemistry and Molecular Genetics, The University of Illinois, Chicago, Illinois, USA
  6. 6Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  7. 7Department of Pediatrics, The University of Illinois, Chicago, Illinois, USA
  8. 8Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, China
  9. 9Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  10. 10Department of Medicine, University of Chicago, Chicago, Illinois, USA
  11. 11Department of Medicine, University of Arizona, Tucson, Arizona, USA
  1. Correspondence to Viswanathan Natarajan, COMRB Building, Room # 3137, 909, South Wolcott Avenue, Chicago, IL 60612, USA; visnatar{at}uic.edu

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.

  • Idiopathic pulmonary fibrosis

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