ANTIAPOPTOTIC MECHANISMS OF NO IN THE LIVER

点击翻译按钮获取中文摘要

Nitric oxide (NO) is a biologic mediator that participates in many physiological and pathophysiological processes. Under normal conditions, liver produces low levels of NO by the constitutive endothelium NO synthase (eNOS). However, high quantities of NO are generated in the liver during acute inflammation via the induction of the inducible NOS. Cytokines, including TNFalpha, are also produced and believed to contribute to the extensive hepatocellular injury in fulminant hepatic failure via initiating hepatic apoptosis and necrosis. Recent data have shown that NO actually is cytoprotective and that applying NO to the liver blocks subsequent liver damage. Therefore NO appears to be an important endogenous inhibitor of apoptosis in the liver. Investigation of the anti-apoptotic mechanisms of NO may provide new clues for clinical implications in preventing organ failure during fulminant hepatic failure, transplant rejection, and sepsis. Furthermore, NO may contribute to tumor growth by preventing apoptosis of malignant cells. The apoptotic signaling pathway in primary hepatocytes will be determined in this proposal. The involvement of specific caspases, Bcl-2 family members, and mitochondria in death signaling pathways will be defined. The mechanisms by which NO and cGMP regulate and interfere with the hepatocyte apoptosis pathway will then be determined at each of the three levels.