A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

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• 作者：Sravanthi Gundavarapu ; Jianguo Zhuang ; Edward G. Barrett ; Fadi Xu ; Robert G. Russell ; Mohan L. Sopori
• 关键词：Sarin ; Bronchoconstriction ; Epinephrine ; Oxygen therapy ; Respiratory function ; Inflammatory cytokines
• 刊名：Toxicology and Applied Pharmacology
• 出版年：15 January, 2014
• 年：2014
• 卷：274
• 期：2
• 页码：200-208
• 全文大小：1312 K

文摘

Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD₅₀ sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1伪, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD₅₀ sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1伪, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD₅₀ sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin.