The Role of Hepatic Sinusoidal Cells in the Development of Massive Liver Necrosis

Abstract

Massive liver necrosis develops as a result of microcirculatory disturbance due to fibrin deposition in the hepatic sinusoids through the derangement of blood coagulation equilibrium. Such mechanisms might be involved in the development of fulminant viral hepatitis as well as primary graft nonfunction following orthotopic liver transplantation. In rat models of massive liver necrosis, fibrin deposition occurred in association with endothelial cell injury in the hepatic sinusoids. Such endothelial cell injury was caused by hepatic stellate cell damage or activation of Kupffer cells and hepatic macrophages. Activated Kupffer cells and hepatic macrophages produced sinusoidal fibrin deposition in two different ways. When hepatic macrophages were activated through a cytokine network of interleukin (IL)-18, interferon (IFN)-γ, and IL-2, they expressed increased CD14, a receptor for lipopolysaccharide and its binding protein complex, and destroyed sinusoidal endothelial cells by releasing cytotoxic mediators such as tumor necrosis factor (TNF)-α and superoxide anions following endotoxin stimulation. In contrast, Kupffer cells activated by overloading of gut-derived substances showed marked expression of tissue factor, an initiator of the blood coagulation cascade. Although such Kupffer cells expressed less CD 14 and cytotoxic mediators, they provoked sinusoidal fibrin deposition following endotoxin stimulation. The hepatic sinusoids have the unique characteristic that endothelial cells express minimal tissue factor pathway inhibitor and thrombomodulin compared with those in other organs. This may contribute to the development of sinusoidal fibrin deposition in both models. Thus, the supplementation with both factors would be a therapeutic strategy for massive liver necrosis associated with sinusoidal fibrin deposition. Also, selective bowel decontamination to inhibit bacterial translocation into the portal blood would be a promising candidate.