Laboratório da Disciplina de Emergências Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Shock. 2011 Jun;35(6):560-6. doi: 10.1097/SHK.0b013e31820fe5d5.
Excessive free-radical production due to various bacterial components released during bacterial infection has been linked to cell death and tissue injury. Peroxynitrite is a highly reactive oxidant produced by the combination of nitric oxide (NO) and superoxide anion, which has been implicated in cell death and tissue injury in various forms of critical illness. Pharmacological decomposition of peroxynitrite may represent a potential therapeutic approach in diseases associated with the overproduction of NO and superoxide. In the present study, we tested the effect of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Mice were injected i.p. with LPS 40 mg/kg with or without FP15 [Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin] (0.1, 0.3, 1, 3, or 10 mg/kg per hour). Mice were killed 12 h later, followed by the harvesting of samples from the lung, liver, and gut for malondialdehyde and myeloperoxidase measurements. In other subsets of animals, blood samples were obtained by cardiac puncture at 1.5, 4, and 8 h after LPS administration for cytokine (TNF-α, IL-1β, and IL-10), nitrite/nitrate, alanine aminotransferase, and blood urea nitrogen measurements. Endotoxemic animals showed an increase in survival from 25% to 80% at the FP15 doses of 0.3 and 1 mg/kg per hour. The same dose of FP15 had no effect on plasma levels of nitrite/nitrate. There was a reduction in liver and lung malondialdehyde in the endotoxemic animals pretreated with FP15, as well as in hepatic myeloperoxidase and biochemical markers of liver and kidney damage (alanine aminotransferase and blood urea nitrogen). In a bacterial model of sepsis induced by cecal ligation and puncture, FP15 treatment (0.3 mg/kg per day) significantly protected against mortality. The current data support the view that peroxynitrite is a critical factor mediating liver, gut, and lung injury in endotoxemia and septic shock: its pharmacological neutralization may be of therapeutic benefit.
由于细菌感染过程中释放的各种细菌成分导致自由基的过度产生，与细胞死亡和组织损伤有关。过氧亚硝酸盐是一种由一氧化氮（NO）和超氧阴离子结合产生的高反应性氧化剂，它与各种形式的危重病中的细胞死亡和组织损伤有关。过氧亚硝酸盐的药理分解可能代表与 NO 和超氧阴离子过度产生相关的疾病的一种潜在治疗方法。在本研究中，我们在脂多糖（LPS）诱导的内毒素血症和脓毒症的小鼠模型中测试了一种强效过氧亚硝酸盐分解催化剂的效果。小鼠经腹腔注射 LPS 40mg/kg，同时给予 FP15[Fe(III) 四（2-（N-三乙基亚乙二醇单甲醚）吡啶基）卟啉]（0.1、0.3、1、3 或 10mg/kg/小时）。12 小时后处死小鼠，然后从肺、肝和肠道中采集样本，用于丙二醛和髓过氧化物酶测量。在其他亚组动物中，通过心脏穿刺在 LPS 给药后 1.5、4 和 8 小时采集血液样本，用于细胞因子（TNF-α、IL-1β 和 IL-10）、亚硝酸盐/硝酸盐、丙氨酸氨基转移酶和血尿素氮测量。内毒素血症动物的存活率从 25%增加到 80%，FP15 剂量为 0.3 和 1mg/kg/小时。相同剂量的 FP15 对内毒素血症动物的血浆亚硝酸盐/硝酸盐水平没有影响。FP15 预处理的内毒素血症动物的肝脏和肺部丙二醛减少，肝和肺髓过氧化物酶以及肝和肾损伤的生化标志物（丙氨酸氨基转移酶和血尿素氮）减少。在盲肠结扎和穿刺诱导的细菌性脓毒症模型中，FP15 治疗（0.3mg/kg/天）显著降低死亡率。目前的数据支持这样一种观点，即过氧亚硝酸盐是介导内毒素血症和感染性休克中肝、肠和肺损伤的关键因素：其药理中和可能具有治疗益处。
