Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte αMβ2 integrin-dependent upregulation of Mmp12

JOURNAL OF HEPATOLOGY

卷:66

Article

Kopec, Anna K.^1,3  Joshi, Nikita^2,3  Cline-Fedewa, Holly¹  Wojcicki, Anna V.¹  Ray, Jessica L.¹  Sullivan, Bradley P.^1,4  Froehlich, John E.^5,6  Johnson, Brendan F.⁵  Flick, Matthew J.⁷  Luyendyk, James P.^1,2,3 

[1] Michigan State Univ, Dept Pathobiol & Diagnost Investigat, E Lansing, MI 48824 USA

[2] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA

[3] Michigan State Univ, Inst Integrat Toxicol, E Lansing, MI 48824 USA

[4] Pfizer Inc, Lake Forest, IL USA

[5] Michigan State Univ, Dept Energy, Plant Res Lab, E Lansing, MI 48824 USA

[6] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA

[7] Cincinnati Childrens Hosp, Div Expt Hematol & Canc Biol, Canc & Blood Dis Inst, Cincinnati, OH USA

关键词: Blood coagulation;    Hemostasis;    Fibrinogen;    Liver repair;    Macrophages;    Inflammation;    alpha(M)beta(2);    Metalloproteinase;    Acetaminophen;    Fibrin.;   

DOI  :  10.1016/j.jhep.2016.12.004

来源: Elsevier

【 摘 要 】

Background & Aims: Acetaminophen (APAP)-induced liver injury is coupled with activation of the blood coagulation cascade and fibrin(ogen) accumulation within APAP-injured livers of experimental mice. We sought to define the role of fibrin(ogen) deposition in APAP-induced liver injury and repair. Methods: Wild-type, fibrinogen-deficient mice, mutant mice with fibrin(ogen) incapable of binding leukocyte alpha(M)beta(2) integrin (Fib gamma(390-396A) mice) and matrix metalloproteinase 12 (Mmp12)-deficient mice were fasted, injected with 300 mg/kg APAP i.p. and evaluated at a range of time-points. Plasma and liver tissue were analyzed. Rescue of Fib gamma(390-396A) mice was carried out with exogenous Mmp12. To examine the effect of the allosteric leukocyte integrin alpha(M)beta(2) activator leukadherin-1 (LA-1), APAP-treated mice were injected with LA-1. Results: In wild-type mice, APAP overdose increased intrahepatic levels of high molecular weight cross-linked fibrin(ogen). Anticoagulation reduced early APAP hepatotoxicity (6 h), but increased hepatic injury at 24 h, 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 h) and unresolved hepatocellular necrosis (48 and 72 h). Fib gamma(390-396A) mice had decreased hepatocyte proliferation and increased multiple indices of liver injury, suggesting a mechanism related to fibrin(ogen)-leukocyte interaction. Induction of Mmp12, was dramatically reduced in APAP-treated Fib gamma(390-396A) mice. Mice lacking Mmp12 displayed exacerbated APAP-induced liver injury, resembling Fib gamma(390-396A) mice. In contrast, administration of LA-1 enhanced hepatic Mmp12 mRNA and reduced necrosis in APAP-treated mice. Further, administration of recombinant Mmp12 protein to APAP-treated Fib gamma(390-396A) mice restored hepatocyte proliferation. Conclusions: These studies highlight a novel pathway of liver repair after APAP overdose, mediated by fibrin(ogen)-alpha(M)beta(2) integrin engagement, and demonstrate a protective role of Mmp12 expression after APAP overdose. Lay summary: Acetaminophen overdose leads to activation of coagulation cascade and deposition of high molecular weight cross-linked fibrin(ogen) species in the liver. Fibrin(ogen) is required for stimulating liver repair after acetaminophen overdose. The mechanism whereby fibrin(ogen) drives liver repair after acetaminophen overdose requires engagement of leukocyte alpha(M)beta(2) integrin and subsequent induction of matrix metalloproteinase 12. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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