Atropine for chlorine inhalation toxicity

 描述（由申请方提供）：氯是一种强效呼吸道和肺部刺激物，暴露后可引起浓度依赖性损伤。它是吸入有毒物质中最常见的物质之一。与急性氯吸入相关的临床表现包括轻度接触时的眼睛和喉咙刺激，较高浓度时心肺症状不断升级。暴露于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、心脏肥大，并可能导致死亡。目前对急性氯气损伤的治疗在迅速去污后仅仅是对症治疗。氯吸入后引起急性死亡的损伤机制知之甚少，也几乎没有研究。当吸入的氯与粘膜和气道表面的水反应时，会发生呼吸道损伤，形成盐酸（HCl）和次氯酸（HOCl），一种强氧化剂。氯还与蛋白质反应形成氯化衍生物（氯胺），这是具有相当大氧化潜力的长寿命产品。据信，氯发挥其毒性， 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，这一切如何在暴露后几分钟到几小时内导致死亡的机制尚不清楚。最近的研究表明，气道刺激性感觉受体，即瞬时受体电位（TRP）通道，参与传播损伤。对HOCl和氯胺作用的新研究揭示了它们改变几种重要酶功能的潜力，包括乙酰胆碱酯酶（AChE）的失活。乙酰胆碱酯酶抑制导致毒蕈碱受体的持续激活，引起胆碱能过度刺激的症状，包括支气管收缩、支气管收缩、心动过缓、心脏收缩力差、肺动脉高压、全身血管舒张和心肺衰竭的可能性。据报道，受害者在大量接触氯后出现了所有这些症状。我们实验室的初步数据证实，大鼠在接触高剂量氯后，乙酰胆碱酯酶受到严重抑制，同时出现“胆碱能毒性”症状，通常随后死亡。因此，除了从HOCl和氯胺的氧化损伤，AChE酶的失活和由此产生的副交感神经/胆碱能/毒蕈碱途径过度刺激可以发挥重要作用，氯诱导的死亡率和发病率。我们的假设是，阿托品，FDA批准的抗胆碱能抢救药物，将提高生存率和扭转与高剂量氯暴露相关的严重发病率，特别是改善心肺功能。为测试其作为单一急救药物的潜力，暴露后将肌内注射阿托品。我们还将评估阿托品在该模型中发挥疗效的可能机制。该应用将开发用于大量氯吸入后现场救援的实用药剂。

 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.