ANTIAPOPTOTIC MECHANISMS OF NO IN THE LIVER

一氧化氮(NO)是一种生物介质，参与了许多 生理和病理生理过程。在正常情况下， 肝脏通过构成内皮细胞产生低水平的NO 合酶(ENOS)。然而，在空气中会产生大量的NO 肝脏在急性炎症过程中通过诱导诱导型一氧化氮合酶。 细胞因子，包括肿瘤坏死因子α，也被产生并被认为是 暴发性肝广泛肝细胞损伤的原因 通过启动肝细胞凋亡和坏死而失败。最近的数据显示 表明NO实际上具有细胞保护作用，并且将NO应用于 肝脏会阻止随后的肝脏损伤。因此，NO似乎是一种 肝脏中重要的内源性细胞凋亡抑制因子。调查 NO抗细胞凋亡机制的研究可能为临床提供新的线索 预防暴发性器官衰竭的临床意义 肝功能衰竭、移植排斥反应和败血症。此外，不可以 通过阻止肿瘤细胞的凋亡而促进肿瘤生长。 原代肝细胞中的凋亡信号通路将是 在这项提案中确定。特定的半胱氨酸酶的参与， BCL-2家族成员，以及死亡信号通路中的线粒体将 被定义。NO和cGMP的调控和干预机制 与肝细胞的凋亡途径将确定在每个 三个层次中的一个。

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.