ANTIAPOPTOTIC MECHANISMS OF NO IN THE LIVER

NO在肝脏中的抗凋亡机制

• 批准号: 6138324
• 负责人: JIANRONG LI
• 金额: $ 1.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6138324
• 关键词: CD95 molecule; apoptosis; biological signal transduction; cell growth regulation; cysteine endopeptidases; cytoprotection; human tissue; liver; liver cells; liver pharmacology; mitochondria; nitric oxide; nitric oxide synthase; tumor necrosis factor alpha

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.

一氧化氮 (NO) 是一种生物介质，参与许多过程 生理和病理生理过程。在正常情况下， 肝脏通过内皮细胞 NO 产生低水平的 NO 合酶（eNOS）。 然而，体内会产生大量的NO。 肝脏在急性炎症期间通过诱导型 NOS 的诱导。 细胞因子，包括 TNFα，也被产生并被认为是 导致暴发性肝病的广泛肝细胞损伤 通过引发肝细胞凋亡和坏死而失败。 最近的数据有 表明NO实际上具有细胞保护作用，并且将NO应用于 肝脏可以阻止随后的肝脏损伤。 因此，NO 似乎是 肝脏细胞凋亡的重要内源性抑制剂。调查 NO抗凋亡机制的研究可能为研究提供新的线索 暴发期预防器官衰竭的临床意义 肝衰竭、移植排斥和败血症。 此外，NO 可能 通过防止恶性细胞凋亡来促进肿瘤生长。 原代肝细胞中的凋亡信号通路是 本提案中确定。 特定半胱天冬酶的参与， Bcl-2家族成员和死亡信号通路中的线粒体将 被定义。 NO和cGMP调节和干扰的机制 然后将在每个 三个级别中的。