SKL-2841, a dual antagonist of MCP-1 and MIP-1 beta, prevents bleomycin-induced skin sclerosis in mice.
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.
Kimura
Mizuho
M
Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
Kawahito
Yutaka
Y
Hamaguchi
Masahide
M
Nakamura
Takashi
T
Okamoto
Masayuki
M
Matsumoto
Yukiharu
Y
Endo
Hirahito
H
Yamamoto
Aihiro
A
Ishino
Hidetaka
H
Wada
Makoto
M
Omoto
Atsushi
A
Tsubouchi
Yasunori
Y
Kohno
Masataka
M
Yoshikawa
Toshikazu
T
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
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D001761:Bleomycin