The Role of Plasminogen Activator Inhibitor Type-1 in Fibrosis
The Role of Plasminogen Activator Inhibitor Type-1 in Fibrosis
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DOI：
10.1055/s-0036-1586228
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发表时间：
2017-03-01
影响因子：
5.7
通讯作者：
Vaughan, Douglas
中科院分区：
文献类型：
--
作者：
Flevaris, Panagiotis;Vaughan, Douglas
创伤愈合期间细胞外基质（ECM）沉积是对损伤的生理反应。伤口愈合在慢性损伤或长期代谢疾病的情况下变得失调，导致ECM组分的积累和纤维化。基质蛋白周转率由合成速率以及蛋白水解降解速率和基质金属蛋白酶（MMP）清除率决定。间质肌成纤维细胞的持续活化，加上基质蛋白水解的缺陷，最终破坏组织结构，并导致生化和机械器官功能障碍，最终器官衰竭。纤溶酶原激活物抑制剂-1（派-1）通过抑制纤溶酶介导的MMP活化来调节组织稳态和伤口愈合。使用肝、肺和肾纤维化模型的多个报告表明派-1缺陷或派-1活性的抑制减弱纤维化。纤溶酶介导的MMP活化的去抑制导致胶原降解及其减少的积累，导致这些器官中纤维化基质沉积的减少。有趣的是，派-1的纯合缺陷促进年龄依赖性自发性心脏纤维化，表明派-1在心脏中的保护作用。目前尚不清楚派-1缺陷的心脏成纤维细胞是否具有增加的增殖、迁移或分化能力，这使得它们能够克服增加的纤溶酶和MMP活性和基质清除。本文综述了派-1在肺、肝、肾和心血管系统等不同器官纤维化中的作用。
Extracellular matrix (ECM) deposition during wound healing is a physiological response to an insult. Wound healing becomes deregulated in the setting of chronic injury or long-standing metabolic disease, leading to the accumulation of ECM components and fibrosis. Matrix protein turnover is determined by the rate of synthesis as well as the rate of proteolytic degradation and clearance by matrix metalloproteinases (MMPs). The persistent activation of interstitial myofibroblasts, coupled with defects in matrix proteolysis, ultimately disrupts tissue architecture and leads to biochemical and mechanical organ dysfunction with eventual organ failure. Plasminogen activator inhibitor type-1 (PAI-1) regulates tissue homeostasis and wound healing by inhibiting plasmin-mediated MMP activation. Multiple reports using models of liver, lung, and kidney fibrosis suggest that PAI-1 deficiency or inhibition of PAI-1 activity attenuates fibrosis. The disinhibition of plasmin-mediated MMP activation leads to collagen degradation and its diminished accumulation, resulting in the reduction of fibrotic matrix deposition in these organs. Paradoxically, homozygous deficiency of PAI-1 promotes age-dependent spontaneous cardiac fibrosis, suggesting a protective role for PAI-1 in the heart. It remains unclear whether PAI-1-deficient cardiac fibroblasts have increased proliferative, migratory, or differentiation capabilities, that allow them to overcome increased plasmin and MMP activity and matrix clearance. In this review, we examine the specific roles of PAI-1 in fibrosis of different organs including the lung, liver, kidney, and cardiovascular system.