BIOCHEMICAL MECHANISMS OF OXIDATIVE INJURY IN TRAUMA

创伤氧化损伤的生化机制

• 批准号: 6107527
• 负责人: ULLA G. KNAUS
• 金额: $ 15.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107527
• 关键词: NAD(P)H dehydrogenase; cellular pathology; endotoxins; enzyme activity; enzyme induction /repression; guanosinetriphosphatases; human tissue; laboratory mouse; leukocyte oxidative burst; lipopolysaccharides; mitogen activated protein kinase; molecular pathology; neutrophil; nuclear factor kappa beta; oxidative stress; phagocytes; phosphatidate; posttraumatic stress disorder; septic shock; wound infection

The Rac GTPase-controlled NADPH oxidase of human phagocytes is responsible for the formation of superoxide anion and other oxidants used by these cells for bacterial killing, and is also an important contributor to the inflammatory response. NADPH oxidase is directly stimulated by LPS in monocytes, and LPS serves to "prime" oxidant production in other leukocytes, thereby enhancing the inflammatory damage occurring during septic shock. We will investigate the connections between Rac GTPase-regulated responses of leukocytes and the signaling mechanisms utilized by LPS. Novel lipid mediators formed in response to LPS will be tested for the ability to disrupt regulatory complexes of Rho family GTPases and RhoGDI. We will use both direct binding measurements and activity assays to evaluate possible effects on Rac signing by this mechanism. The contribution of Rac to the phagocyte oxidative responses induced by 125 will be tested using genetic approaches. Signaling via Rac to p38 MAPK will be examined as well, and we will evaluate the hypothesis that Rac- regulated kinases such as p38 control the coordinated assembly of the NADPH oxidase. Sites on NADPH oxidase components that are phosphorylated by p38 will be identified, and the contribution of this enzyme to oxidase assembly assessed. Finally, the possible connection of Rac GTPase to activation of the LPS- and cytokine-regulated transcription factor NF-kB will be evaluated. These studies should clarify the mechanisms by which LPS mediates inflammatory tissue damage during septic shock syndromes.

人吞噬细胞的Rac GTP酶控制的NADPH氧化酶是 负责形成超氧阴离子和其他氧化剂 这些细胞用来杀死细菌，也是一种重要的 炎症反应的贡献者。NADPH氧化酶直接 在单核细胞中由LPS刺激，并且LPS用于“引发”氧化剂 在其他白细胞中产生，从而增强炎症反应。 败血性休克时发生的损伤。我们将调查 Rac GTP酶调节的白细胞反应与 LPS利用的信号传导机制。 将测试响应于LPS而形成的新型脂质介质， 破坏Rho家族GTP酶的调节复合物的能力， RhoGDI。我们将使用直接结合测量和活性测定 评估这种机制对Rac签名的可能影响。的 Rac对125诱导的吞噬细胞氧化反应的贡献 将通过基因方法进行测试。通过Rac向p38 MAPK的信号传导 我们也将研究，我们将评估假设，即Rac- 受调节的激酶如p38控制细胞的协调组装， NADPH氧化酶。NADPH氧化酶组分上磷酸化的位点 p38将被确定，这种酶的贡献， 评估氧化酶组装。最后，Rac的可能连接 GT3对LPS和精氨酸调节的转录的激活 将评估因子NF-κ B。这些研究应澄清 LPS介导炎症组织损伤的机制 败血性休克综合征