Site,severity& Infection Type Influence On Superoxide Di

在感染过程中，超氧阴离子的产生是白细胞、血管内皮和其他功能所必需的。然而，在脓毒症和感染性休克期间，超氧化物及其反应物的过量产生与组织损伤和器官功能障碍的发病机制有关。对动物模型组织样本的检查也表明，败血症期间内源性抗氧化剂（如超氧化物歧化酶）的消耗可能会加剧这种损伤。因此，采用低分子量非蛋白膜渗透性超氧化物歧化酶模拟物的抗氧化治疗已被开发用于败血症和其他与全身性炎症增加相关的疾病。这些药物是金属螯合的大环配体配合物，具有类似超氧化物歧化酶的自由基清除活性。M40401和M40403对超氧阴离子本身表现出新的选择性。然而，超氧阴离子在脓毒症中可能有不同的作用。除了在微生物杀灭和继发性炎症组织损伤方面的相反作用外，超氧化物还可能以相反的方式改变血液动力学功能。过量的超氧化物的产生与内源性和外源性儿茶酚胺的氧化有关，这通常会导致血管收缩。另一方面，超氧阴离子有助于一氧化氮（一种有效的血管扩张剂）的失活。因此，超氧阴离子对血管张力的总体影响可能代表了它对儿茶酚胺对一氧化氮失活的相对贡献。根据脓毒症的严重程度，这些贡献可能有所不同。反过来，M40401等超氧化物抑制剂的血流动力学作用也可能受到脓毒症潜在严重程度的影响。本研究调查了感染挑战的严重程度及其相关的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，动物被随机分配给静脉注射大肠杆菌的剂量，以产生低或高的控制死亡率，然后用M40401或安慰剂治疗。结果表明，M40401的疗效取决于控制死亡率。在对照死亡率高的实验中（即中位数为>），M40401提高了存活率和平均动脉血压，并降低了血小板计数。然而，在低对照死亡率的实验中(即：

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.