Nitrite therapy improves survival postexposure to chlorine gas
Nitrite therapy improves survival postexposure to chlorine gas
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DOI：
10.1152/ajplung.00079.2014
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发表时间：
2014-12-01
影响因子：
4.9
通讯作者：
Patel, Rakesh P.
中科院分区：
文献类型：
--
作者：
Honavar, Jaideep;Doran, Stephen;Patel, Rakesh P.
在因意外或故意释放而造成大规模伤亡的情况下，可能会接触相对较高浓度的氯 (Cl-2) 气体。最近的研究表明，气道、肺和全身脉管系统存在显着的暴露后损伤，部分是由氧化应激、炎症和内源性一氧化氮稳态途径功能障碍介导的。然而，需要能够在现场快速且容易地施用并且对氯暴露后的毒性表现出功效的治疗剂。在这项研究中，我们测试了在 Cl-2 暴露后通过肌肉注射使用亚硝酸盐补充一氧化氮是否可以预防 Cl-2 气体毒性。 C57bl/6 雄性小鼠暴露于百万分之 600 的 Cl-2 气体中 45 分钟，并在暴露后肌内注射或不注射亚硝酸盐的情况下测定 24 小时存活率。暴露后 30 或 60 分钟单次注射亚硝酸盐 (10 mg/kg) 可显着提高 24 小时存活率（从大约 20% 提高到 50%）。生存与气道中中性粒细胞积累减少有关。在暴露于 Cl-2 之前使小鼠中性粒细胞减少可以提高生存率并导致亚硝酸盐依赖性生存保护的丧失。有趣的是，与雄性小鼠相比，雌性小鼠对 Cl-2 诱导的毒性更敏感，并且对暴露后亚硝酸盐治疗的反应也较差。这些数据提供了疗效证据，并定义了在 Cl-2 气体暴露后单次肌肉注射亚硝酸盐作为治疗剂的治疗参数，适合在大规模伤亡情况下给药。
Exposure to relatively high levels of chlorine (Cl-2) gas can occur in mass-casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl-2 exposure, could prevent Cl-2 gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl-2 gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from similar to 20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl-2 exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl-2-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl-2 gas exposure that is amenable to administration in mass-casualty scenarios.