Site,severity& Infection Type Influence On Superoxide Di

地点、严重程度

• 批准号: 6683812
• 负责人: Peter Q Eichacker
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6683812
• 关键词: antiinflammatory agents; bacterial disease; biological models; biomimetics; biotherapeutic agent; blood toxicology; enzyme activity; inflammation; injury /disease stressor; laboratory rat; microorganism growth; oxidative stress; pharmacokinetics; superoxide dismutase; synthetic enzyme

Superoxide anion production is necessary for leukocyte, vascular endothelial and other functions during infection. However, excessive production of superoxide and its reactant products has been implicated in the pathogenesis of tissue injury and organ dysfunction occurring during sepsis and septic shock. Examination of tissue samples in animal models has also suggested that depletion of endogenous antioxidants such as superoxide dismutase during sepsis may potentiate this injury. As a result, antioxidant treatments employing low molecular weight nonprotein membrane-permeable superoxide dismutase mimetics have been developed for use in sepsis and other conditions associated with increased systemic inflammation. These agents which are metal-chelated macrocyclic ligand complexes, demonstrate free radical scavenging activities similar to superoxide dismutase. M40401 and M40403 are two such agents which show novel selectivity for superoxide anion itself. Superoxide anion however may have divergent effects during sepsis. In addition to the opposing roles superoxide might have on microbial killing and secondary inflammatory tissue injury, it also has the potential to alter hemodynamic function in opposing ways. Excessive superoxide production has been implicated in the oxidation of both endogenous and exogenous catecholamines which normally cause vasoconstriction. On the other hand, superoxide anion contributes to the inactivation of nitric oxide, a potent vasodilator. As a result, the overall effects of superoxide anion on vascular tone may represent its relative contribution to the inactivation of catecholamines versus nitric oxide. These contributions may vary during sepsis dependent on its severity. In turn, the hemodynamics effects of superoxide inhibitors like M40401 may also be influenced by the underlying severity of sepsis. The present studies investigated whether the severity of infectious challenge and its associated risk of death would alter the efficacy of M40401 in a rat model of sepsis. In individual experiments, animals were randomized to be challenged with doses of intravenous E. coli designed to produce low or high control mortality rates, following which they were treated with M40401 or placebo. The results showed that the efficacy of M40401 was dependent on control mortality rates. In experiments with high control mortality rates (i.e. > median), M40401 increased survival rates and mean arterial blood pressure and decreased platelet counts. However in experiments with low control mortality rates (i.e.

超氧阴离子的产生是感染时白细胞、血管内皮等功能所必需的。然而，超氧化物及其反应产物的过量产生与脓毒症和脓毒性休克期间发生的组织损伤和器官功能障碍的发病机制有关。在动物模型中的组织样本的检查也表明，内源性抗氧化剂，如超氧化物歧化酶在脓毒症的消耗可能会加强这种损伤。因此，采用低分子量非蛋白质膜渗透性超氧化物歧化酶模拟物的抗氧化剂治疗已被开发用于败血症和与全身炎症增加相关的其他病症。这些试剂是金属螯合大环配体络合物，表现出类似于超氧化物歧化酶的自由基清除活性。M40401和M40403是两种对超氧阴离子本身具有新颖选择性的试剂。 然而，超氧阴离子在脓毒症期间可能具有不同的作用。除了超氧化物可能对微生物杀灭和继发性炎症组织损伤具有相反的作用外，它还可能以相反的方式改变血液动力学功能。过量的超氧化物产生与内源性和外源性儿茶酚胺的氧化有关，这通常会引起血管收缩。另一方面，超氧阴离子有助于一氧化氮的失活，一氧化氮是一种有效的血管扩张剂。因此，超氧阴离子对血管张力的总体影响可能代表其对儿茶酚胺与一氧化氮失活的相对贡献。这些贡献在脓毒症期间可能根据其严重程度而变化。反过来，超氧化物抑制剂如M40401的血液动力学效应也可能受到脓毒症潜在严重程度的影响。 本研究研究了感染性攻毒的严重程度及其相关死亡风险是否会改变M40401在脓毒症大鼠模型中的疗效。在单独的实验中，动物被随机分配接受静脉注射E。大肠杆菌设计，以产生低或高的控制死亡率，然后他们与M40401或安慰剂治疗。结果表明，M40401的功效取决于控制死亡率。在对照死亡率较高（即>中位数）的实验中，M40401可增加存活率和平均动脉血压，并降低血小板计数。然而，在具有低对照死亡率的实验中（即，