title: Treatment with alpha-galactosylceramide attenuates the development of bleomycin-induced pulmonary fibrosis.
abstract: Pulmonary fibrosis is an end-stage disorder for which efficacious therapeutic options are not readily available. Although its pathogenesis is poorly understood, pulmonary fibrosis occurs as a result of various inflammations. NKT cells modulate inflammation because of their ability to produce large amounts of cytokines by stimulation with their glycolipid ligand. In the present study, we investigated the effects of alpha-galactosylceramide (alpha-GalCer), a selective NKT cell ligand, on the development of bleomycin-induced pulmonary fibrosis. Treatment of mice with alpha-GalCer prolonged their survival under bleomycin administration by attenuating the development of pulmonary fibrosis. The protective effects of alpha-GalCer were associated with an increase in the pulmonary level of IFN-gamma and a decrease in the pulmonary level of fibrogenic cytokines such as TGF-beta and connective tissue growth factor. The initial pulmonary inflammation caused by bleomycin was also attenuated by alpha-GalCer with the reduction of the macrophage inflammatory protein-2 level. The protective effects of alpha-GalCer were markedly reduced in mice lacking NKT cells or as a result of treatment with anti-IFN-gamma Ab. These results suggest that alpha-GalCer suppresses bleomycin-induced acute pulmonary inflammation and thus attenuates the development of pulmonary fibrosis possibly by regulating several cytokine levels.
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Tennoudai, Tsukuba, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.forename: Akira
authors.initials: A
authors.lastname: Shibuya
authors.forename: Kazuko
authors.initials: K
authors.lastname: Shibuya
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Mie
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Hegab
authors.forename: Tohru
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Sekizawa
mesh_terms: D000208:Acute Disease; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001761:Bleomycin / Q000633:toxicity*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007442:Intubation, Intratracheal; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; C526318:CCN2 protein, mouse; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D005699:Galactosylceramides; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D007371:Interferon-gamma; C103873:KRN 7000