CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis

被引:109
作者
Gharaee-Kermani, M
McCullumsmith, RE
Charo, IF
Kunkel, SL
Phan, SH [1 ]
机构
[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA
[4] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
关键词
chemokine; chemokine receptor; inflammation; pulmonary fibrosis; TGF-beta;
D O I
10.1016/j.cyto.2003.08.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MCP-1, which signals via the CC chemokine receptor 2 (CCR2), is induced in lung fibrosis that is accompanied by mononuclear cell recruitment and activation of lung fibroblasts. To evaluate the role of CCR2 in lung fibrosis, CCR2 knockout (ko) mice were used in a model of bleomycin-induced lung fibrosis. Wild type (wt) and ko mice were injected endotracheally with bleomycin to induce lung injury and fibrosis, and then analyzed for degree of lung fibrosis and cytokine expression. The results showed significantly reduced fibrosis in ko mice as evidenced by decreased lung type I collagen gene expression and hydroxyproline content relative to those in wt mice. Lung TNF-alpha and TGF-beta1 expression was significantly lower in ko vs. wt. mice, while MCP-1 expression was unaffected. Interestingly, lung alpha-smooth muscle actin (alpha-SMA) expression, a marker for myofibroblast differentiation, was also decreased in ko mice, which was confirmed by analysis of isolated lung fibroblasts. Fibroblasts from ko mice exhibited decreased responsiveness to TGF-beta1 induced alpha-SMA expression, which was associated with reduced expression of TGF-beta receptor II (TbetaRII) and Smad3. These findings suggest that CCR2 signaling plays a key role in bleomycin-induced pulmonary fibrosis by regulating fibrogenic cytokine expression and fibroblast responsiveness to TGF-beta. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:266 / 276
页数:11
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