Hepatic Microcirculation in Massive Liver Necrosis and Liver Regeneration

Abstract

Sinusoidal endothelial cells in the liver are unique in blood coagulation regulatory function, as they express minimal anticoagulants, such as tissue factor pathway inhibitor (TFPI) and thrombomodulin. Thus, fibrin deposition can easily occur in the hepatic sinusoids when Kupffer cells or hepatic macrophages are activated to increase the activity of tissue factor, an initiator of blood coagulation cascade. Such deposition seems to be involved in the development of massive liver necrosis through microcirculatory disturbance in patients with fulminant hepatic failure and primary graft nonfunction after orthotopic liver transplantation. Anticoagulant therapies targeting the hepatic sinusoids using recombinant human TFPI and bowel decontamination with polymyxin B sulfate are promising methods to prevent these liver injuries. Endothelial cells and hepatocytes are markedly injured in massive liver necrosis with fibrin deposition in the hepatic sinusoids, suggesting that endothelial cell proliferation may be critical for sufficient liver regeneration. Vascular endothelial growth factor (VEGF) derived from activated Kupffer cells, macrophages, and stellate cells can induce capillarization of the hepatic sinusoids through vascular endothelial cell proliferation along with actions of platelet-derived growth factor and fibroblast growth factor-2. In contrast, VEGF from regenerating hepatocytes seems essential for reconstruction of the hepatic sinusoids, as sinusoidal endothelial cells can proliferate only by action of VEGF. Thus, a communication system between endothelial cells and other liver cells may play an important role in the development of and recovery from massive liver necrosis.