Synergism between platelets and leukocytes in inducing endothelial cell apoptosis in the cold ischemic rat liver: a Kupffer cell mediated injury

Abstract

ABSTRACT Sinusoidal endothelial cell (SEC) apoptosis is the hallmark of early reperfusion injury in liver transplantation. Platelet sequestration occurs after transplantation and causes SEC apoptosis. Leukocytes also adhere to the liver upon reperfusion. Their role and interaction with platelets in inducing SEC apoptosis are unknown. Kupffer cells possibly interact with circulating cells; therefore, they could be involved in inducing SEC apoptosis. We tested the hypothesis that platelets and leukocytes synergistically induce SEC apoptosis through a Kupffer‐cell‐dependent mechanism. Livers were preserved for 24 h in cold University of Wisconsin solution and were reperfused in an isolated perfused rat liver model with perfusate containing red blood cells and either platelets, leukocytes, or both. In some experiments, Kupffer cells were inhibited by either gadolinium chloride or pentoxifylline. Apoptosis was determined after reperfusion by terminal deoxynucleotidyl transferase‐mediated nick‐end labeling and electron microscopy. Leukocytes and platelets were rapidly sequestered into the liver and induced SEC apoptosis. The presence of both platelet and leukocyte adhesion was associated with a dramatic increase in SEC apoptosis compared with liver reperfused with the use of one population of circulating elements or in absence of both platelets and leukocytes. In liver reperfused with platelets and leukocytes, SEC apoptosis was completely abrogated by either modality of Kupffer cell inhibition. Platelets and leukocytes induce SEC apoptosis upon reperfusion of cold preserved liver through a Kupffer‐cell‐dependent mechanism.