Protective effects of matrix metalloproteinase-12 following corneal injury
Protective effects of matrix metalloproteinase-12 following corneal injury
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DOI：
10.1242/jcs.28033
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发表时间：
2013-09-01
影响因子：
4
通讯作者：
Werb, Zena
中科院分区：
文献类型：
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作者：
Chan, Matilda F.;Li, Jing;Werb, Zena
因损伤导致的角膜瘢痕是全球失明的主要原因，它是伤口愈合过程中炎症和血管生成失调的结果。在此我们证明细胞外基质金属蛋白酶MMP12（巨噬细胞金属弹性蛋白酶）是这些修复过程的重要调节因子。化学损伤导致Mmp12（-/-）小鼠角膜中纤维化标志物α -平滑肌肌动蛋白和I型胶原蛋白的表达更高，并且血管生成水平增加，相比野生型小鼠的角膜。在体内，我们通过共聚焦成像观察到Mmp12（-/-）角膜中免疫细胞动态发生改变。我们确定这种动态改变是炎症反应改变的结果，在第一天中性粒细胞浸润延迟，6天后巨噬细胞浸润过度，分别由趋化因子CXCL1和CCL2的表达水平改变所介导。抑制这些趋化因子后角膜修复恢复正常。综上所述，这些数据表明MMP12通过调节免疫细胞浸润和血管生成在伤口修复过程中对角膜纤维化具有保护作用。
Corneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers alpha-smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of Mmp12(-/-) mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in Mmp12(-/-) corneas by confocal imaging. We determined that the altered dynamics were the result of an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration 6 days later, mediated by altered expression levels of chemokines CXCL1 and CCL2, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data show that MMP12 has a protective effect on corneal fibrosis during wound repair through regulation of immune cell infiltration and angiogenesis.