Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice.
Hepatic ischemia and reperfusion (I/R) leads to the formation of leukocyte-platelet aggregates. Upon activation, platelets generate reactive oxygen species and release proapoptotic and proinflammatory mediators as well as growth factors. In cold hepatic ischemia, adhesion of platelets to endothelial cells mediates sinusoidal endothelial cell apoptosis. Furthermore, platelet-derived serotonin mediates liver regeneration. We hypothesized that platelets may contribute to reperfusion injury and repair after normothermic hepatic ischemia. The aim of this study was to assess the impact of platelets in normothermic hepatic I/R injury using models of impaired platelet function and immune thrombocytopenia. Inhibition of platelet function in mice was achieved via clopidogrel feeding. Immune thrombocytopenia was induced via intraperitoneal injection of anti-CD41 antibody. Platelet-derived serotonin was investigated using mice lacking tryptophan hydroxylase 1. Mice were subjected to 60 minutes of partial hepatic ischemia and various time points of reperfusion. Hepatic injury was determined via AST and histological analysis of the necrotic area as well as leukocyte infiltration. Liver regeneration was determined via proliferating cell nuclear antigen and Ki67 immunohistochemistry. Neither inhibition of platelet function nor platelet depletion led to a reduction of I/R injury. Liver regeneration and repair were significantly impaired in platelet-depleted animals. Mice lacking peripheral serotonin were deficient in hepatocyte proliferation, but otherwise displayed normal tissue remodeling.


CONCLUSIONS
Platelets have no direct impact on the pathogenesis of normothermic I/R injury. However, they mediate tissue repair and liver regeneration. Furthermore, platelet-derived serotonin is a mediator of hepatocyte proliferation in the postischemic liver, but has no impact on tissue remodeling.
Nocito
Antonio
A
Department of Visceral and Transplantation Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital Zurich, Zurich, Switzerland,
Georgiev
Panco
P
Dahm
Felix
F
Jochum
Wolfram
W
Bader
Michael
M
Graf
Rolf
R
Clavien
Pierre-Alain
PA
D000818:Animals; D001792:Blood Platelets / Q000473:pathology / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010976:Platelet Count; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D012701:Serotonin / Q000502:physiology*; D013696:Temperature; D013921:Thrombocytopenia / Q000473:pathology; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase