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 生理和病理生理过程。在正常情况下， 肝脏通过组成性内皮NO产生低水平的NO 合成酶（eNOS）。 然而，大量的NO产生于空气中。 肝脏急性炎症时通过诱导型NOS的诱导。 细胞因子，包括TNF α，也会产生，并被认为是 在暴发性肝病中， 通过启动肝细胞凋亡和坏死而衰竭。 最近的数据 表明NO实际上是细胞保护性的， 肝脏可以阻止随后的肝损伤。 因此，NO似乎是一个 肝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NO的抗凋亡作用提供新的线索。 预防暴发期器官衰竭的临床意义 肝衰竭、移植排斥和败血症。 此外，NO可以 通过阻止恶性细胞的凋亡来促进肿瘤生长。 原代肝细胞中的凋亡信号传导途径将是 在这个提案中， 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 与肝细胞凋亡途径，然后将确定在每个 的三个层次。