Biomol Ther.  2019 May;27(3):318-326. 10.4062/biomolther.2018.131.

Deficiency of Sphingosine-1-Phosphate Receptor 2 (S1Pâ‚‚) Attenuates Bleomycin-Induced Pulmonary Fibrosis

• Park SJ
• Im DS

• KMID: 2447859
• DOI: http://doi.org/10.4062/biomolther.2018.131

Abstract

Sphingosine 1-phosphate (S1P) levels are often found to be elevated in serum, bronchoalveolar lavage, and lung tissue of idiopathic pulmonary fibrosis patients and experimental mouse models. Although the roles of sphingosine kinase 1 and S1P receptors have been implicated in fibrosis, the underlying mechanism of fibrosis via Sphingosine 1-phosphate receptor 2 (S1P₂) has not been fully investigated. Therefore, in this study, the roles of S1P₂ in lung inflammation and fibrosis was investigated by means of a bleomycin-induced lung fibrosis model and lung epithelial cells. Bleomycin was found to induce lung inflammation on day 7 and fibrosis on day 28 of treatment. On the 7(th) day after bleomycin administration, S1P₂ deficient mice exhibited significantly less pulmonary inflammation, including cell infiltration and pro-inflammatory cytokine induction, than the wild type mice. On the 28(th) day after bleomycin treatment, severe inflammation and fibrosis were observed in lung tissues from wild type mice, while lung tissues from S1P₂ deficient mice showed less inflammation and fibrosis. Increase in TGF-β1-induced extracellular matrix accumulation and epithelial-mesenchymal transition were inhibited by JTE-013, a S1P₂ antagonist, in A549 lung epithelial cells. Taken together, pro-inflammatory and pro-fibrotic functions of S1P₂ were elucidated using a bleomycin-induced fibrosis model. Notably, S1P₂ was found to mediate epithelial-mesenchymal transition in fibrotic responses. Therefore, the results of this study indicate that S1P₂ could be a promising therapeutic target for the treatment of pulmonary fibrosis.

Keyword

Fibrosis; Inflammation; Lung; Sphingosine 1-phosphate; S1Pâ‚‚

MeSH Terms

Animals
Bleomycin
Bronchoalveolar Lavage
Epithelial Cells
Epithelial-Mesenchymal Transition
Extracellular Matrix
Fibrosis
Humans
Idiopathic Pulmonary Fibrosis
Inflammation
Lung
Mice
Phosphotransferases
Pneumonia
Pulmonary Fibrosis*
Receptors, Lysosphingolipid*
Sphingosine
Bleomycin
Phosphotransferases
Receptors, Lysosphingolipid
Sphingosine