Atropine for chlorine inhalation toxicity

 说明(申请人提供)：氯是一种强烈的呼吸系统和肺部刺激物，暴露后会引起浓度依赖的损伤。它是有毒吸入中最常见的物质之一。与急性氯气吸入有关的临床表现包括轻度接触时眼睛和喉咙刺激，高浓度时心肺症状加重。接触大量的氯会导致严重的低氧血症、呼吸困难、支气管收缩、急性肺损伤、心脏增大，并可能导致死亡。目前对迅速净化后的急性氯气损伤的治疗只是对症处理。氯气吸入后损伤导致急性死亡的机制(S)知之甚少，研究也很少。当吸入的氯与粘膜和呼吸道表面的水反应，形成盐酸(HCl)和次氯酸(HOCl)，这是一种强大的氧化剂时，暴露后对呼吸道的伤害就会发生。氯还与蛋白质反应生成氯化衍生物(氯胺)，这是一种具有相当大氧化潜力的长寿产品。据信，氯具有毒性。 通过氯本身、HOCl和氯胺的氧化特性以及呼吸道粘膜的酸化对人体组织的影响。然而，这一切如何导致接触几分钟到几个小时内死亡的机制尚不清楚。最近的研究表明，呼吸道刺激性感觉受体，即瞬时受体电位(TRP)通道，参与了传播性损伤。对HOCl和氯胺影响的新研究发现，它们有可能改变几种重要的酶功能，包括使乙酰胆碱酯酶(AChE)失活。AChE抑制会导致M受体的持续激活，导致胆碱能过度刺激的症状，包括支气管炎、支气管收缩、心动过缓、心脏收缩能力差、肺动脉高压、全身血管扩张，以及潜在的心肺衰竭。据报道，在大量接触氯气后，受害者出现了所有这些症状。我们实验室的初步数据证实，大鼠在高剂量氯气暴露后出现严重的AChE抑制，并伴有‘胆碱能毒素’的迹象，通常伴随着死亡。因此，除了HOCl和氯胺的氧化损伤外，AChE酶的失活和由此产生的副交感/胆碱能/毒扁豆碱通路的过度刺激可能在氯诱导的死亡和发病率中起主要作用。我们的假设是，阿托品，一种FDA批准的抗胆碱能抢救药物，将提高存活率，逆转与高剂量氯暴露相关的严重并发症，特别是心肺功能的改善。为了测试其作为单一救援剂的潜力，暴露后将肌肉注射阿托品。我们还将评估阿托品在该模型中发挥疗效的可能潜在机制。这项应用将开发实用的药剂(S)，用于大量吸入氯气后的野战救援。

 DESCRIPTION (provided by applicant): Chlorine is a potent respiratory and pulmonary irritant that causes concentration-dependent injury after exposure. It is one of the most common substances involved in toxic inhalation. The clinical picture associated with acute chlorine inhalation includes eye and throat irritation in mild exposures, with escalating cardiopulmonary symptoms at higher concentrations. Exposure to massive amounts of chlorine results in profound hypoxemia, dyspnea, bronchoconstriction, acute lung injury, cardiomegaly, and may result in death. Current treatment of acute chlorine gas injury after prompt decontamination is merely symptomatic. The mechanism(s) of injury causing acute mortality after chlorine inhalation are poorly understood and scarcely studied. Injury to the respiratory tract after exposure occurs when inhaled chlorine reacts with water on the surface of mucus membranes and airways, forming hydrochloric acid (HCl) and hypochlorous acid (HOCl), a powerful oxidant. Chlorine also reacts with proteins to form chlorinated derivatives (chloramines), which are long-lived products with considerable oxidizing potential. It is believed that chlorine exerts its toxic effects on human tissue via oxidative properties of chlorine itself, HOCl and chloramines, and also from acidification of respiratory mucosa. However, the mechanism as to how all this would lead to death within minutes to hours of exposure is not known. Recent studies have suggested the involvement of airway irritant sensory receptors, i.e. transient receptor potential (TRP) channels, in propagating injury. New research into the effects of HOCl and chloramines uncovered their potential to modify several vital enzymatic functions, including the inactivation o acetylcholinesterase (AChE). AChE inhibition results in sustained activation of muscarinic receptors, causing symptoms of cholinergic overstimulation, consisting of bronchorrhea, bronchoconstriction, bradycardia, poor cardiac contractility, pulmonary hypertension, systemic vasodilation, and potential for cardiopulmonary failure. All these symptoms have been reported in victims after massive chlorine exposure. Preliminary data from our laboratory confirmed severe AChE inhibition after high dose chlorine exposure in rats, with concurrent signs of `cholinergic toxidrome", often followed by death. Therefore, in addition to oxidative damage from HOCl and chloramines, the inactivation of the AChE enzyme and the resultant parasympathetic/ cholinergic/ muscarinic pathway overstimulation could play a major role in chlorine-induced mortality and morbidity. Our hypothesis is that atropine, an FDA-approved anticholinergic rescue drug, will improve survival and reverse serious morbidity associated with high dose chlorine exposure, with particular improvement in cardiopulmonary function. To test its potential as a single rescue agent, atropine will be given intramuscularly after exposure. We will also evaluate possible underlying mechanisms by which atropine may exert its efficacy in this model. This application will develop practical agent(s) for field rescue after significant chlorine inhalation.