title: Hepatocyte tissue factor activates the coagulation cascade in mice.
abstract: In this study, we characterized tissue factor (TF) expression in mouse hepatocytes (HPCs) and evaluated its role in mouse models of HPC transplantation and acetaminophen (APAP) overdose. TF expression was significantly reduced in isolated HPCs and liver homogenates from TF(flox/flox)/albumin-Cre mice (HPC(ΔTF) mice) compared with TF(flox/flox) mice (control mice). Isolated mouse HPCs expressed low levels of TF that clotted factor VII-deficient human plasma. In addition, HPC TF initiated factor Xa generation without exogenous factor VIIa, and TF activity was increased dramatically after cell lysis. Treatment of HPCs with an inhibitory TF antibody or a cell-impermeable lysine-conjugating reagent prior to lysis substantially reduced TF activity, suggesting that TF was mainly present on the cell surface. Thrombin generation was dramatically reduced in APAP-treated HPC(ΔTF) mice compared with APAP-treated control mice. In addition, thrombin generation was dependent on donor HPC TF expression in a model of HPC transplantation. These results suggest that mouse HPCs constitutively express cell surface TF that mediates activation of coagulation during hepatocellular injury.
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kopec
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.forename: Holly
authors.initials: H
authors.lastname: Cline
authors.forename: Juliette A
authors.initials: JA
authors.lastname: Brown
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Bishop
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kassel
authors.forename: Cheryl
authors.initials: C
authors.lastname: Rockwell
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000418:Albumins / Q000235:genetics; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D015942:Factor VIIa / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000502:physiology*
chemical_list: D000418:Albumins; D018712:Analgesics, Non-Narcotic; D012333:RNA, Messenger; D000082:Acetaminophen; D013925:Thromboplastin; C045073:Cre recombinase; D019426:Integrases; D015942:Factor VIIa; D013917:Thrombin