Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice
Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice
复制标题
DOI：
10.2152/jmi.60.127
复制
发表时间：
2013-02-01
影响因子：
0.7
通讯作者：
Nishioka, Yasuhiko
中科院分区：
文献类型：
--
作者：
Makino, Hideki;Aono, Yoshinori;Nishioka, Yasuhiko
据报道，循环纤维细胞迁移到受伤的肺部，并通过包括CXCL12-CXCR4轴在内的趋化因子-趋化因子受体系统促进纤维形成。在这里，我们假设阻断CXCR4可能会抑制纤维细胞向受损肺的迁移和随后的肺纤维化。为了探索阻断CXCR4的抗纤维化作用，我们在博莱霉素诱导的小鼠肺纤维化模型中使用了CXCR4的特异性拮抗剂AMD3100。给药AMD3100显著改善了博来霉素治疗小鼠的体重减轻，并抑制了肺胸膜下区纤维化病变。定量分析表明，AMD3100治疗可降低肺内胶原蛋白含量和纤维化评分（Aschcroft评分）。虽然AMD3100在第7天对支气管肺泡灌洗液的细胞分类没有影响，但在第14天，AMD3100降低了淋巴细胞的百分比。AMD3100在体外直接抑制人纤维细胞对CXCL12的迁移，在体内减少博霉素处理后纤维细胞向肺的运输。这些结果表明，通过抑制循环纤维细胞的迁移，阻断CXCR4可能是治疗肺纤维化患者的有效策略。
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.