title: Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice.
abstract: Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makino
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.forename: Momoyo
authors.initials: M
authors.lastname: Azuma
authors.forename: Masami
authors.initials: M
authors.lastname: Kishi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yokota
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Akio
authors.initials: A
authors.lastname: Takezaki
authors.forename: Jun
authors.initials: J
authors.lastname: Kishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawano
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ogawa
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D000818:Animals; D001596:Benzylamines; D001761:Bleomycin / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000032:analysis; D002633:Chemotaxis / Q000187:drug effects; D000080027:Cyclams; D005260:Female; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D001761:Bleomycin; C088327:plerixafor