Treatment of persistent chlorine-induced small airway disease

氯气是一种剧毒的呼吸道刺激物，被认为是一种化学威胁剂，因为它 它可能会在工业事故或恐怖袭击中释放。氯的急性效应 吸入包括呼吸困难、低氧血症、肺炎和肺水肿。长期后果 氯吸入包括肺功能损害和结构变化， 在一些暴露的个体中观察到。我们的合作者Erik Sauvsen博士记录了肺 功能异常的人群中的个人谁是暴露于氯的结果，大 2005年发生在南卡罗来纳州Graniteville的意外释放。结果表明， 疾病状态，但表明一个重要组成部分涉及小气道疾病。的障碍 制定持续性氯致肺病的对策是缺乏相关的动物 功效测试模型。我们的初步数据表明，兔子暴露于氯，并检查7 天后表现出小气道的炎症，并发展为散发性闭塞性病变， 闭塞性细支气管炎（BO）。这些动物表现出正常的基线肺阻力，但表现出 对吸入乙酰甲胆碱反应过度根据这些初步数据，我们建议扩大这些 研究开发一种模型，其中小气道的闭塞性变化更广泛， 如在暴露于氯气的人体中观察到的，基线肺阻力增加。我们将 然后评估一个潜在的对策的效力时，管理后，氯暴露， 预防小气道疾病。待检验的假设为：1）增加暴露后 监测时间和/或氯剂量将产生广泛的小气道BO损伤， 基线肺阻力显著增加;和2）用吸入性皮质类固醇加地塞米松治疗， 氯暴露后的肾上腺素能激动剂将抑制BO病变和异常肺的发展 功能具体目标1将是开发持续性氯诱导的肺病的动物模型， 复制了在接触氯的人中观察到的疾病状态。具体目标2将是评估 目前可用的治疗（吸入性皮质类固醇加长效β-肾上腺素能激动剂）在兔模型， 持续性氯中毒性肺病这些探索性研究将产生有价值的信息 为对抗措施测试开发适当的动物模型，并将生成初始数据 关于目前用于刺激物诱发哮喘的一种治疗方法的疗效， 作为一种对策。

Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea, hypoxemia, pneumonitis, and pulmonary edema. Longer term consequences of chlorine inhalation include both pulmonary function impairment and structural changes that have been observed in some exposed individuals. Our collaborator Dr. Erik Svendsen has documented pulmonary function abnormalities in a population of individuals who were exposed to chlorine as a result of a large accidental release that occurred in Graniteville, SC in 2005. The results point to a spectrum of respiratory disease states, but suggest that an important component involves small airway disease. An impediment to developing countermeasures for persistent chlorine-induced lung disease is the lack of a relevant animal model for efficacy testing. Our preliminary data indicate that rabbits exposed to chlorine and examined 7 days later exhibit inflammation of the small airways and develop sporadic obliterative lesions characteristic of bronchiolitis obliterans (BO). These animals exhibited normal baseline lung resistance but exhibited hyperreactivity to inhaled methacholine. Based on these preliminary data, we propose to expand on these studies to develop a model in which the obliterative changes to small airways are more widespread resulting in increased baseline lung resistance as has been observed in humans exposed to chlorine gas. We will then assess the efficacy of a potential countermeasure when administered following chlorine exposure for the prevention of small airway disease. The hypotheses to be tested are: 1) Increasing post-exposure monitoring time and/or chlorine dose will produce widespread small airway BO lesions that result in significant increases in baseline lung resistance; and 2) Treatment with inhaled corticosteroid plus ß- adrenergic agonist after chlorine exposure will inhibit the development of BO lesions and abnormal lung function. Specific Aim 1 will be to develop an animal model of persistent chlorine-induced lung disease that replicates the disease states observed in chlorine-exposed humans. Specific Aim 2 will be to evaluate a currently available therapy (inhaled corticosteroid plus long-acting ß-adrenergic agonist) in a rabbit model of persistent chlorine-induced lung disease. These exploratory studies will generate valuable information toward development of an appropriate animal model for countermeasure testing and will generate initial data regarding efficacy of a type of treatment currently used for irritant-induced asthma that could be readily adopted as a countermeasure.