Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte α(M)β(2) integrin-dependent upregulation of Mmp12.
Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte α(M)β(2) integrin-dependent upregulation of Mmp12.
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DOI：
10.1016/j.jhep.2016.12.004
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发表时间：
2017-04
影响因子：
25.7
通讯作者：
Luyendyk JP
中科院分区：
文献类型：
--
作者：
Kopec AK;Joshi N;Cline-Fedewa H;Wojcicki AV;Ray JL;Sullivan BP;Froehlich JE;Johnson BF;Flick MJ;Luyendyk JP
Acetaminophen (APAP)-induced liver injury is coupled to activation of the blood coagulation cascade and fibrin(ogen) accumulation within APAP-injured livers of experimental mice. We sought to define the precise role of fibrin(ogen) deposition in APAP-induced liver injury and repair. Fasted mice were injected with 300 mg/kg APAP i.p. and evaluated various times later. In wild-type mice APAP overdose increased intrahepatic levels of high molecular weight cross-linked fibrin(ogen). Anticoagulation reduced early APAP hepatotoxicity (6 hours), but surprisingly, increased hepatic injury at 24 hours, implying a protective role for coagulation at the onset of repair. Complete fibrin(ogen) deficiency delayed liver repair after APAP overdose, evidenced by a reduction of proliferating hepatocytes (24 hours) and unresolved hepatocellular necrosis (48 and 72 hours). Mutant mice with fibrin(ogen) incapable of binding leukocyte αMβ2 integrin (Fibγ390-396A mice) had decreased hepatocyte proliferation and increases in multiple indices of liver injury, suggesting a mechanism related to fibrin(ogen)-leukocyte interaction. Induction of the macrophage-associated gene, matrix metalloproteinase 12 (Mmp12), was dramatically reduced in APAP-treated Fibγ390-396A mice, and mice lacking Mmp12 displayed exacerbated APAP-induced liver injury, resembling Fibγ390-396A mice. In contrast, administration of the αMβ2 integrin allosteric agonist leukadherin-1 enhanced hepatic MMP12 mRNA and reduced necrosis in APAP-treated mice. Further, administration of recombinant MMP12 protein to APAP-treated Fibγ390-396A mice restored hepatocyte proliferation. Collectively, these studies highlight an entirely novel pathway of liver repair after APAP overdose, mediated by fibrin(ogen)-αMβ2 integrin engagement and demonstrate for the first time a protective role of Mmp12 expression after APAP overdose.
