title: Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.
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.
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kohno
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kadoya
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hidetake
authors.initials: H
authors.lastname: Nagahara
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Fujii
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Rheumatic Diseases and Joint Function, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seno
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Aihiro
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Department of Orthopedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Oda
authors.affiliation: Department of Orthopedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Rheumatic Diseases and Joint Function, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Orthopedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakada
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.affiliation: Inflammation and Immunology, Graduate school of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawahito
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid; D005355:Fibrosis / Q000235:genetics*; D007249:Inflammation / Q000235:genetics*; D008168:Lung / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D049349:Receptors, Lysosphingolipid / Q000235:genetics*; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D001761:Bleomycin