title: Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.
abstract: BACKGROUND
  The coagulation cascade has been shown to participate in chronic liver injury and fibrosis, but the contribution of various thrombin targets, such as protease activated receptors (PARs) and fibrin(ogen), has not been fully described. Emerging evidence suggests that in some experimental settings of chronic liver injury, platelets can promote liver repair and inhibit liver fibrosis. However, the precise mechanisms linking coagulation and platelet function to hepatic tissue changes following injury remain poorly defined.
  
  
  OBJECTIVE
  To determine the role of PAR-4, a key thrombin receptor on mouse platelets, and fibrin(ogen) engagement of the platelet αII b β3 integrin (αIIb β3 ) in a model of cholestatic liver injury and fibrosis.
  
  
  METHODS
  Biliary and hepatic injury was characterized following 4 week administration of the bile duct toxicant α-naphthylisothiocyanate (ANIT) (0.025%) in PAR-4-deficient mice, mice expressing a mutant form of fibrin(ogen) incapable of binding integrin αII b β3 (Fibγ(Δ5) ), and wild-type mice.
  
  
  RESULTS
  Elevated plasma thrombin-antithrombin and serotonin levels, hepatic fibrin deposition, and platelet accumulation in liver accompanied hepatocellular injury and fibrosis in ANIT-treated wild-type mice. PAR-4 deficiency reduced plasma serotonin levels, increased serum bile acid concentration, and exacerbated ANIT-induced hepatocellular injury and peribiliary fibrosis. Compared with PAR-4-deficient mice, ANIT-treated Fibγ(Δ5) mice displayed more widespread hepatocellular necrosis accompanied by marked inflammation, robust fibroblast activation, and extensive liver fibrosis.
  
  
  CONCLUSIONS
  Collectively, the results indicate that PAR-4 and fibrin-αII b β3 integrin engagement, pathways coupling coagulation to platelet activation, each exert hepatoprotective effects during chronic cholestasis.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA; Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: N
authors.initials: N
authors.lastname: Joshi
authors.forename: A K
authors.initials: AK
authors.lastname: Kopec
authors.forename: K M
authors.initials: KM
authors.lastname: O'Brien
authors.forename: K L
authors.initials: KL
authors.lastname: Towery
authors.forename: H
authors.initials: H
authors.lastname: Cline-Fedewa
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
authors.forename: B L
authors.initials: BL
authors.lastname: Copple
authors.forename: M J
authors.initials: MJ
authors.lastname: Flick
authors.forename: J P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D015058:1-Naphthylisothiocyanate; D000818:Animals; D000990:Antithrombin III; D001647:Bile Acids and Salts / Q000097:blood; D001777:Blood Coagulation / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002779:Cholestasis / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009336:Necrosis; D010447:Peptide Hydrolases / Q000097:blood; D010641:Phenotype; D015539:Platelet Activation / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D018179:Receptors, Thrombin / Q000172:deficiency / Q000235:genetics; D012701:Serotonin / Q000097:blood; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; D015241:Fibrinogens, Abnormal; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018179:Receptors, Thrombin; C046193:antithrombin III-protease complex; D012701:Serotonin; D015058:1-Naphthylisothiocyanate; D000990:Antithrombin III; D010447:Peptide Hydrolases; C112908:protease-activated receptor 4
keywords: blood coagulation; fibrin; fibrosis; liver disease; platelets