Therapeutics against chemical threat induced respiratory toxicity

针对化学威胁引起的呼吸道毒性的治疗

• 批准号: 7224704
• 负责人: Madhusoodana P. Nambiar
• 金额: $ 58.02万
• 依托单位: GENEVA FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224704
• 关键词: asthma; bioterrorism /chemical warfare; comorbidity; disease /disorder model; environmental exposure; environmental toxicology; guinea pigs; hazardous substances; histology; lung injury; nerve gas; pathologic process; pulmonary respiration; respiratory epithelium; respiratory function; respiratory toxin; therapy design /development; vapor

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.

描述(申请人提供)：直接肺损伤和肺部并发症是两伊战争中有毒化学品暴露、印度博帕尔异氰酸甲酯意外泄漏、东京地铁沙林袭击和莫斯科人质危机后死亡的主要原因。这些悲剧表明，人类的呼吸道是多么容易受到空气中化学品的影响，并暗示呼吸管理对于拯救生命是最重要和最关键的。以前的报告表明，化学损伤与直接化学反应、随后的急性呼吸窘迫综合征和晚期并发症有关。大量平民和越来越多患有哮喘等既往疾病的儿童更容易受到化学威胁剂的伤害。我们建议在动物模型上研究吸入致命性化学威胁物质沙林后的呼吸毒性和肺损伤。我们最近开发的吸入性暴露的微量滴注技术将用于沙林蒸气暴露。微量滴注技术绕过了啮齿动物呼吸道中化学威胁物质的解毒，因为啮齿动物的呼吸道中含有高水平的羧酸酯酶和粘液。因此，化学制剂到达肺泡，并模拟类似于人类的暴露。呼吸毒性将通过毒理学、生化、组织病理学和呼吸功能分析进行评估。还将评估肺损伤的时间顺序。我们将确定支气管肺泡灌洗、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FDA批准或正在进行临床试验的一些药物以及新的治疗方案进行评估，以开发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既往疾病动物模型中的呼吸毒性。将评估潜在的治疗方法对哮喘模型中沙林暴露的保护作用。拟议的研究将确定呼吸毒性和肺损伤的生化机制，这些机制在化学威胁剂诱导的毒性和接触正常人群和有既往疾病的脆弱人群后的主要死亡原因中发挥核心作用。对于大规模情况，将迅速开发有效的治疗方法，以防止肺部毒性及其长期后果，以补充现有的模式。