Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan; Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan.
Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
Am J Pathol. 2018 May;188(5):1204-1212. doi: 10.1016/j.ajpath.2018.01.010. Epub 2018 Feb 16.
Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear. We tested the hypothesis that PAI-1 limits liver-related morbidity after APAP challenge by reducing tPA-dependent fibrinolysis. Compared with APAP-challenged (300 mg/kg) wild-type mice, hepatic deposition of cross-linked fibrin was reduced, with intrahepatic congestion and hemorrhage increased in PAI-1-deficient mice 24 hours after APAP overdose. Administration of recombinant wild-type human PAI-1 reduced intrahepatic hemorrhage 24 hours after APAP challenge in PAI-1 mice, whereas a mutant PAI-1 lacking antiprotease function had no effect. Of interest, tPA deficiency alone did not affect APAP-induced liver damage. In contrast, fibrinolysis, intrahepatic congestion and hemorrhage, and mortality driven by PAI-1 deficiency were reduced in APAP-treated tPA/PAI-1 double-knockout mice. The results identify PAI-1 as a critical regulator of intrahepatic fibrinolysis in experimental liver injury. Moreover, the results suggest that the balance between PAI-1 and tPA activity is an important determinant of liver pathology after APAP overdose.
对乙酰氨基酚（APAP）诱导的小鼠肝损伤与凝血级联的激活和纤维蛋白在肝内的沉积有关。纤溶酶原激活物抑制剂-1（PAI-1）是组织型纤溶酶原激活物（tPA）的重要生理抑制剂，在纤溶过程中发挥关键作用。PAI-1 在实验性 APAP 诱导的肝损伤和急性肝衰竭患者中均有增加。先前的研究表明，PAI-1 可防止 APAP 挑战后的肝内出血和死亡率，但下游机制尚不清楚。我们假设 PAI-1 通过减少 tPA 依赖性纤维蛋白溶解来限制 APAP 挑战后的肝相关发病率。与 APAP 挑战（300mg/kg）的野生型小鼠相比，PAI-1 缺陷型小鼠在 APAP 过量后 24 小时内肝内交联纤维蛋白沉积减少，肝内淤血和出血增加。在 PAI-1 小鼠中给予重组野生型人 PAI-1 可减少 APAP 挑战后 24 小时的肝内出血，而缺乏抗蛋白酶功能的突变型 PAI-1 则没有作用。有趣的是，tPA 缺陷本身并不影响 APAP 诱导的肝损伤。相比之下，在 APAP 处理的 tPA/PAI-1 双敲除小鼠中，PAI-1 缺乏引起的纤维蛋白溶解、肝内淤血和出血以及死亡率降低。结果表明 PAI-1 是实验性肝损伤中肝内纤维蛋白溶解的关键调节剂。此外，结果表明 PAI-1 和 tPA 活性之间的平衡是 APAP 过量后肝病理的重要决定因素。
