Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice

Abstract

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. Conclusion: 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. (HEPATOLOGY 2007;45:369-376.)

Cellular and molecular mechanisms in liver fibrogenesis

“…By using the conventional procedure of 70% partial hepatectomy (PHX) as a model to induce liver regeneration it has been described that, following surgical intervention, serotonin is rapidly mobilized from gut and accumulates in the remnant liver, possibly delivered here by platelets [148], although the latter hypothesis has been recently challenged. Available data suggest in any case that 5-HT can sustain hepatocyte proliferation following PHX, likely by acting through a restrict number of receptors (5-HT1A, 2A and 2B), as also unequivocally indicated by the significant impairment of regeneration observed in Tph−/− mice [147,148]. Recently, it has proposed that cholangiocytes may represent an additional source of serotonin as resident liver cells, with serotonin that once released can in turn represses cholangiocyte proliferation through a negative feedback mechanism [149].…”

Platelet and Liver Regeneration

“…In basic research, Lesurtel et al showed that platelet-derived serotonin mediated liver regeneration in mice (Lesurtel et al, 2006). Nocito et al demonstrated that platelets and platelet-derived serotonin promoted tissue repair after normothermic hepatic ischemia in mice (Nocito et al, 2007). In addition, we have obtained several types of evidence for platelets promoting liver regeneration using different experimental models of liver dysfunction in small and large animals.…”

Blood Platelets and Systemic Sclerosis

“…The role of platelets in tissue repair goes beyond vascular integrity. Indeed, platelets are essential for organ repair and regeneration as remarkably exemplified in the liver [37,[51][52][53].…”