Therapeutics against chemical threat induced respiratory toxicity

描述（由申请方提供）：两伊战争中有毒化学品暴露、印度博帕尔异氰酸甲酯意外释放、东京地铁沙林袭击和莫斯科人质危机后，直接肺损伤伴肺部并发症是大多数死亡原因。这些悲剧表明了人类呼吸道对空气中化学物质的影响是多么敏感，并暗示呼吸管理对于挽救生命是最重要和最关键的。以往的研究表明，化学损伤与直接化学反应有关，随后出现急性呼吸窘迫综合征和晚期并发症。大量平民和越来越多的儿童本来就患有哮喘等疾病，更容易受到化学威胁剂的伤害。我们建议在动物模型中研究吸入致命化学威胁剂沙林后的呼吸毒性和肺损伤。我们最近开发的吸入暴露微滴注技术将用于沙林蒸汽暴露。微量滴注技术绕过了啮齿动物气道中的化学威胁剂的解毒，这些啮齿动物具有高水平的羧酸酯酶和粘液。因此，化学剂到达肺泡并模拟类似于人类的暴露。将通过毒理学、生物化学、组织病理学和呼吸功能分析评估呼吸毒性。还将评估肺损伤的时间顺序。我们将通过支气管肺泡灌洗、血液生物标志物或非侵入性呼吸参数来诊断暴露的严重程度。将对一些FDA批准或临床试验中的治疗方案以及新的治疗方案进行评估，以制定针对肺损伤及其长期后果的有效医学对策。我们还将评估沙林在哮喘等原有疾病的动物模型中的呼吸毒性。将评估潜在的治疗剂在哮喘模型中对沙林暴露的保护作用。拟议的研究将确定呼吸道毒性和肺损伤的生化机制，这些机制在化学威胁物剂诱导的毒性中起着核心作用，也是有健康状况的正常和脆弱人群接触后死亡的主要原因。将为大规模场景迅速开发有效的治疗方法，以防止肺毒性及其长期后果，可以补充现有的模式。

DESCRIPTION (provided by applicant): Direct lung injury, with pulmonary complications, accounted for most of the deaths following toxic chemical exposure in the Iran-Iraq- war, the accidental release of methyl isocyanate in Bhopal, India, the Tokyo subway sarin attack, and the hostage crisis in Moscow. These tragedies exemplify how susceptible human airways are to the effects of airborne chemicals and imply that respiratory management is most important and critical for saving life. Previous reports indicate that chemical injury is associated with direct chemical reaction followed by acute respiratory distress syndrome and late complications. A large number of civilians and an increasing number of children with pre-existing medical conditions such as asthma are more vulnerable to chemical threat agents. We propose to investigate the respiratory toxicity and lung injury following inhalation exposure to the deadly chemical threat agent sarin in animal models. Our recently developed micro-instillation technology of inhalation exposure will be used for sarin vapor exposure. Micro-instillation technology bypasses the detoxification of chemical threat agents in the airway of rodents, which have high levels of carboxylesterase and mucus. Thus, the chemical agents reach alveoli and mimics an exposure similar to human. The respiratory toxicity will be assessed by toxicological, biochemical, histopathological and respiratory functional analysis. The chronology of lung injury will be also assessed. We ill identify bronchoalveolar lavage, blood biomarkers or non-invasive respiratory parameters to diagnose the severity of exposure. A number of FDA-approved or in clinical trial as well as new therapeutic regimens will be evaluated to develop an effective medical countermeasure against pulmonary injury and its long-term consequences. We will also assess the respiratory toxicity of sarin in animals models of pre-existing medical conditions such as asthma. Potential therapeutics will be evaluated for protection against sarin exposure in asthma model. The proposed studies will define the biochemical mechanisms of respiratory toxicity and lung injury that play a central role in chemical threat agent induced toxicity and a major cause of death following exposure in normal and vulnerable populations with pre-existing medical conditions. Effective therapeutics to protect against pulmonary toxicity and its long-term consequences that can complement the existing modalities will be rapidly developed for a mass scenario.