Deficiency of Sphingosine-1-Phosphate Receptor 2 (S1P2) Attenuates Bleomycin-Induced Pulmonary Fibrosis

다국어 초록 (Multilingual 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 7th 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 28th 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.

참고문헌 (Reference)

1 Willis BC, "TGF-beta-induced EMT : mechanisms and implications for fibrotic lung disease" 293 : L525-534, 2007

2 Leask A, "TGF-beta signaling and the fibrotic response" 18 : 816-827, 2004

3 Zhao J, "Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages" 13 : e0197604-, 2018

4 Milara J, "Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition" 67 : 147-156, 2012

5 Kono Y, "Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1" 37 : 395-404, 2007

6 Sobel K, "Sphingosine 1-phosphate(S1P)receptor agonists mediate pro-fibrotic responses in normal human lung fibroblasts via S1P2 and S1P3 receptors and Smad-independent signaling" 288 : 14839-14851, 2013

7 Li C, "Sphingosine 1-phosphate(S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility" 54 : 1205-1213, 2011

8 Ikeda H, "Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2" 50 : 556-564, 2009

9 Park SJ, "Sphingosine 1-phosphate receptor modulators and drug discovery, Biomol" 25 : 80-90, 2017

10 Sonnylal S, "Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis" 62 : 1523-1532, 2010

11 Berend N, "Respiratory disease and respiratory physiology : putting lung function into perspective interstitial lung disease" 19 : 952-959, 2014

12 Shea BS, "Prolonged exposure to sphingosine 1-phosphate receptor-1 agonists exacerbates vascular leak, fibrosis, and mortality after lung injury" 43 : 662-673, 2010

13 Wynn TA, "Mechanisms of fibrosis : therapeutic translation for fibrotic disease" 18 : 1028-1040, 2012

14 Murakami K, "Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model" 9 : e106792-, 2014

15 Li C, "Involvement of sphingosine 1-phosphate(SIP)/S1P3 signaling in cholestasis-induced liver fibrosis" 175 : 1464-1472, 2009

16 Bourke SJ, "Interstitial lung disease : progress and problems" 82 : 494-499, 2006

17 Willis BC, "Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1 : potential role in idiopathic pulmonary fibrosis" 166 : 1321-1332, 2005

18 Masszi A, "Fate-determining mechanisms in epithelial-myofibroblast transition : major inhibitory role for Smad3" 188 : 383-399, 2010

19 Kalluri R, "Epithelial-mesenchymal transition and its implications for fibrosis" 112 : 1776-1784, 2003

20 Kage H, "EMT and interstitial lung disease : a mysterious relationship" 18 : 517-523, 2012

21 Kono M, "Deafness and stria vascularis defects in S1P2 receptor-null mice" 282 : 10690-10696, 2007

22 Dhami R, "Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice" 26 : 749-760, 2010