Abstract
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein–coupled receptors (S1P1–5). Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO)) mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT) mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF) collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF) levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1) or transforming growth factor β1 (TGF-β1) levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.
Highlights
Pulmonary fibrosis is a devastating disorder that is resistant to treatment [1]
We demonstrated that S1P3 deficiency has a significant effect on the pathogenesis of bleomycin-induced pulmonary inflammation and fibrosis
During the acute phase of lung injury, H&E staining revealed less histological evidence of inflammation in the lungs of S1P3 KO mice than in those of WT mice, and analysis of bronchoalveolar lavage fluid (BALF) collected on the seventh day showed that S1P3 KO mice had a 56% reduction in total cell count compared with WT mice
Summary
Initial injury to the lung causes the recruitment of inflammatory cells, release of cytokines, and eventual increase in fibroblast activity, leading to parenchymal remodeling and, fibrosis [2]. Various cytokines and growth factors are involved in these responses, transforming growth factor (TGF-b) is known to play the most essential role in the pathogenesis of lung fibrosis [3]. S1P3 mediates cardiac fibrosis [8] and cholestasis-induced liver fibrosis [9] and some current studies suggest a relationship between S1P3 receptor activity and lung inflammation and fibrosis; the role of S1P3 in the pathogenesis of lung diseases is still poorly understood. We analyzed an in vivo model of bleomycin-induced pulmonary injury in S1P3 KO mice to clarify the role of S1P3 receptor signaling
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