title: Targeting platelet migration in the postischemic liver by blocking protease-activated receptor 4.
abstract: BACKGROUND
  Platelets play a critical role during hepatic ischemia/reperfusion (I/R). Antiplatelet strategies during liver transplantation are, however, limited because of bleeding complications. Thrombin is activated during reperfusion and regulates platelet and endothelial cell function via protease-activated receptor 4 (PAR-4). Interventions at the level of PAR-4, the main platelet receptor for thrombin, are assumed to attenuate the proinflammatory effects of thrombin without affecting blood coagulation. The aim of our study was to analyze the impact of PAR-4 blockade on platelet recruitment and microvascular injury during hepatic I/R.
  
  
  METHODS
  C57BL/6 mice undergoing hepatic I/R (90 min/60 min and 240 min) were treated either with a selective PAR-4 antagonist TcY-NH2 or vehicle. Sham-operated animals served as controls. Recruitment of freshly isolated and fluorescence-labeled platelets and CD4 T cells was analyzed using intravital video fluorescence microscopy. Parameters of tissue injury, regeneration, and blood coagulation were assessed in tissue/blood samples.
  
  
  RESULTS
  Results show that treatment with TcY-NH2 attenuated I/R-induced platelet and CD4 T-cell recruitment, improved sinusoidal perfusion failure, and reduced apoptotic and necrotic injury. The protective effect of PAR-4 blockade did not suppress hemostasis or liver regeneration.
  
  
  CONCLUSIONS
  Our in vivo data suggest PAR-4 as a potential target for future therapeutic strategies against platelet-mediated liver injury on transplantation.
authors.affiliation: 1 Department of Surgery-Grosshadern, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. 2 Walter Brendel Centre of Experimental Medicine, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. 3 Institute of Laboratory Medicine, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. 4 Institute of Pathology, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. 5 Address correspondence to: Andrej Khandoga, M.D., Ph.D., Department of Surgery - Grosshadern Klinikum der Universität München Marchioninistr. 15 81377 Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mende
authors.forename: Jörg
authors.initials: J
authors.lastname: Reifart
authors.forename: Dirk
authors.initials: D
authors.lastname: Rosentreter
authors.forename: Davit
authors.initials: D
authors.lastname: Manukyan
authors.forename: Doris
authors.initials: D
authors.lastname: Mayr
authors.forename: Fritz
authors.initials: F
authors.lastname: Krombach
authors.forename: Markus
authors.initials: M
authors.lastname: Rentsch
authors.forename: Andrej
authors.initials: A
authors.lastname: Khandoga
mesh_terms: D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002450:Cell Communication; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology; D007511:Ischemia / Q000097:blood* / Q000473:pathology; D019394:Ki-67 Antigen / Q000032:analysis; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D016031:Liver Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D015427:Reperfusion Injury / Q000517:prevention & control
chemical_list: D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D018179:Receptors, Thrombin; C112908:protease-activated receptor 4