Local arginase 1 activity is required for cutaneous wound healing.
Local arginase 1 activity is required for cutaneous wound healing.
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DOI：
10.1038/jid.2013.164
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发表时间：
2013-10
影响因子：
6.5
通讯作者：
Hardman, Matthew J.
中科院分区：
文献类型：
--
作者：
Campbell, Laura;Saville, Charis R.;Murray, Peter J.;Cruickshank, Sheena M.;Hardman, Matthew J.
老年人群中的慢性不愈合伤口与长期和过度的炎症反应有关，这被广泛认为会阻碍愈合。先前的研究已经将局部L-精氨酸代谢的改变与病理性伤口愈合联系起来，该改变主要由酶精氨酸酶（Arg）和诱导型一氧化氮合酶（iNOS）介导。在随后的几年中，对Arg/iNOS的兴趣集中在经典与交替激活（M1/M2）巨噬细胞范例上。虽然iNOS在愈合过程中的作用已被研究，但Arg对愈合的贡献仍不清楚。在这里，我们报告说，精氨酸是动态调节在急性伤口愈合。局部精氨酸活性的药理学抑制直接干扰愈合，Tie 2-cre介导的Arg 1缺失也是如此，揭示了Arg 1在愈合过程中的重要性。精氨酸的抑制或耗竭并不改变交替激活的巨噬细胞数量，而是与炎症增加相关，包括iNOS+细胞流入增加和基质沉积缺陷。最后，我们发现，在临床前小鼠模型中，Arg表达减少与延迟愈合直接相关，因此可能代表未来重要的治疗靶点。
Chronic nonhealing wounds in the elderly population are associated with a prolonged and excessive inflammatory response, which is widely hypothesized to impede healing. Previous studies have linked alterations in local L-arginine metabolism, principally mediated by the enzymes arginase (Arg) and inducible nitric oxide synthase (iNOS), to pathological wound healing. Over subsequent years, interest in Arg/iNOS has focused on the classical versus alternatively activated (M1/M2) macrophage paradigm. Although the role of iNOS during healing has been studied, Arg contribution to healing remains unclear. Here, we report that Arg is dynamically regulated during acute wound healing. Pharmacological inhibition of local Arg activity directly perturbed healing, as did Tie2-cre-mediated deletion of Arg1, revealing the importance of Arg1 during healing. Inhibition or depletion of Arg did not alter alternatively activated macrophage numbers but instead was associated with increased inflammation, including increased influx of iNOS+ cells and defects in matrix deposition. Finally, we reveal that in preclinical murine models reduced Arg expression directly correlates with delayed healing, and as such may represent an important future therapeutic target.
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