title: Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice.
abstract: Acetaminophen (APAP)-induced liver injury in humans is associated with robust coagulation cascade activation and thrombocytopenia. However, it is not known whether coagulation-driven platelet activation participates in APAP hepatotoxicity. Here, we found that APAP overdose in mice caused liver damage accompanied by significant thrombocytopenia and accumulation of platelets in the liver. These changes were attenuated by administration of the direct thrombin inhibitor lepirudin. Platelet depletion with an anti-CD41 antibody also significantly reduced APAP-mediated liver injury and thrombin generation, indicated by the concentration of thrombin-antithrombin (TAT) complexes in plasma. Compared with APAP-treated wild-type mice, biomarkers of hepatocellular and endothelial damage, plasma TAT concentration, and hepatic platelet accumulation were reduced in mice lacking protease-activated receptor (PAR)-4, which mediates thrombin signaling in mouse platelets. However, selective hematopoietic cell PAR-4 deficiency did not affect APAP-induced liver injury or plasma TAT levels. These results suggest that interconnections between coagulation and hepatic platelet accumulation promote APAP-induced liver injury, independent of platelet PAR-4 signaling. Moreover, the results highlight a potential contribution of nonhematopoietic cell PAR-4 signaling to APAP hepatotoxicity.
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Miyakawa
authors.affiliation: Institute for Integrative Toxicology, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI; and.
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI; and.
authors.forename: Ryan
authors.initials: R
authors.lastname: Albee
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.
authors.forename: Christina
authors.initials: C
authors.lastname: Brandenberger
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Scott
authors.affiliation: Institute for Integrative Toxicology, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI; and.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.affiliation: Institute for Integrative Toxicology, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI; and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D000990:Antithrombin III / Q000378:metabolism*; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000502:physiology*
chemical_list: D018712:Analgesics, Non-Narcotic; D044462:Receptors, Proteinase-Activated; C046193:antithrombin III-protease complex; C481942:protease-activated receptor 4, mouse; D000082:Acetaminophen; D000990:Antithrombin III; D010447:Peptide Hydrolases