title: E- and P-selectins synergistically inhibit bleomycin-induced pulmonary fibrosis.
abstract: The development of bleomycin-induced lung injury, which is a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. Therefore, bleomycin-induced lung fibrosis was examined in E-selectin-/- mice, P-selectin-/- mice, and E-selectin-/- mice treated with anti-P-selectin monoclonal antibody (mAb) in comparison of wild-type mice. E-selectin-/- mice treated with anti-P-selectin mAb exhibited augmented lung fibrosis histologically, increased lung collagen deposition, and increased mortality compared to wild-type mice. Furthermore, lung interferon-gamma mRNA expression decreased in E-selectin-/- mice treated with anti-P-selectin mAb relative to wild-type mice, while tumor necrosis factor-alpha and interleukin-6 mRNA expression increased in these mice. Similar changes were observed in E-selectin-/- mice, albeit to a lesser extent than those treated with anti-P-selectin mAb. Remarkably, flow cytometric analysis revealed that the frequency of interferon-gamma-producing natural killer T (NKT) cells in the bronchoalveolar lavage was decreased in E-selectin-/- mice and E-selectin-/- mice treated with anti-P-selectin mAb compared with wild-type mice. Moreover, the majority of NKT cells expressed high levels of CXCR3, suggesting that NKT cell infiltration is also dependent on CXCR3 expression. These results suggest that E- and P-selectins synergistically inhibit lung fibrosis by promoting the recruitment of NKT cells.
authors.affiliation: Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Mayuka
authors.initials: M
authors.lastname: Horikawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Hamaguchi
authors.forename: Ayako
authors.initials: A
authors.lastname: Kawasuji
authors.forename: Yukiyo
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Fumihide
authors.initials: F
authors.lastname: Ogawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Steeber
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology / Q000633:toxicity*; D003094:Collagen / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D019040:E-Selectin; D019007:P-Selectin; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D001761:Bleomycin; D003094:Collagen