NADPH oxidase restrains the matrix metalloproteinase activity of macrophages
NADPH oxidase restrains the matrix metalloproteinase activity of macrophages
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DOI：
10.1074/jbc.m503292200
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发表时间：
2005-08-26
影响因子：
4.8
通讯作者：
Heinecke, JW
中科院分区：
文献类型：
--
作者：
Kassim, SY;Fu, XY;Heinecke, JW
基质金属蛋白酶（MMP）在正常和疾病过程中调节许多功能;因此，不可逆地阻断其活性是调节MMP催化的关键步骤。我们以前在体外实验中发现，吞噬细胞产生的氧化中间体通过修饰特定的氨基酸来修饰MMPs。为了评估这种机制是否在体内起作用，我们集中研究了MMP-12，一种已知在小鼠模型中介导肺气肿的巨噬细胞特异性MMP。我们发现，缺乏gp 91（phox），NADPH氧化酶的吞噬细胞特异性成分的小鼠，发展广泛的，自发性肺气肿破坏他们的外周空气空间，而小鼠在NADPH氧化酶和MMP-12都缺乏保护自发性肺气肿。虽然gp 91（phox）-null和野生型巨噬细胞产生同等水平的MMP-12蛋白，氧化剂缺乏的细胞有更大的MMP-12活性比野生型巨噬细胞。这些发现表明，活性中间体提供了一种生理机制，以保护组织免受过度的巨噬细胞介导的损伤，在炎症。
Matrix metalloproteinases ( MMPs) regulate numerous functions in normal and disease processes; thus, irreversibly blocking their activity is a key step in regulating MMP catalysis. We previously showed in vitro that oxidizing intermediates generated by phagocytes inactivate MMPs by modifying specific amino acids. To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models. We found that mice lacking gp91(phox), a phagocyte-specific component of the NADPH oxidase, developed extensive, spontaneous emphysematous destruction of their peripheral air spaces, whereas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema. Although gp91(phox)-null and wild-type macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages. These findings indicate that reactive intermediates provide a physiological mechanism to protect tissues from excessive macrophage-mediated damage during inflammation.