title: SKL-2841, a dual antagonist of MCP-1 and MIP-1 beta, prevents bleomycin-induced skin sclerosis in mice.
abstract: Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis and excessive collagen deposition in the skin and various internal organs. In early stages of SSc, the dermis reveals infiltration of inflammatory cells associated with increased collagen synthesis. SKL-2841 was initially synthesized as a novel small molecule antagonist of MCP-1. In this study, we indicated that SKL-2841 also exerts anti-chemotactic activity for MIP-1 beta in mouse spleen cells. In the early stages of bleomycin-induced skin lesions, immunohistochemical analysis showed the expression of both MCP-1 and MIP-1 beta in dermal inflammatory cells. Moreover, intraperitoneal administration of SKL-2841 suppressed the infiltration of inflammatory mononuclear cells and polymorphonuclear cells in the acute phase and also significantly suppressed fibrillization in the chronic phase in bleomycin-induced scleroderma, compared with PBS treatment. These findings suggest that SKL-2841 has potential as a compound for the treatment of conditions associated with skin fibrosis such as SSc.
authors.affiliation: Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kimura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawahito
authors.forename: Masahide
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okamoto
authors.forename: Yukiharu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Hirahito
authors.initials: H
authors.lastname: Endo
authors.forename: Aihiro
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Ishino
authors.forename: Makoto
authors.initials: M
authors.lastname: Wada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Omoto
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tsubouchi
authors.forename: Masataka
authors.initials: M
authors.lastname: Kohno
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D001761:Bleomycin; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D054407:Chemokine CCL4; D002633:Chemotaxis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D066298:In Vitro Techniques; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D001761:Bleomycin