Treatment of persistent chlorine-induced small airway disease

持续性氯引起的小气道疾病的治疗

• 批准号: 9207953
• 负责人: Gary W. Hoyle
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207953
• 关键词: Acute; Acute Lung Injury; Adopted; Adrenal Cortex Hormones; Adrenergic Agonists; Adverse effects; Affect; Animal Model; Animals; Area; Asthma; Breathing; Bronchiolitis Obliterans; Characteristics; Chemicals; Chlorine; Chronic; Conscious; Data; Development; Disease; Dose; Dyspnea; Exhibits; Exposure to; Fibrosis; Genetic; Goals; Histologic; Hospitals; Human; Hypoxemia; Impairment; Individual; Industrial Accidents; Inflammation; Inflammatory; Investigation; Irritants; Length; Lesion; Long-Term Effects; Lung; Lung diseases; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Oryctolagus cuniculus; Pathology; Poison; Poisoning; Population; Prevention; Pulmonary Edema; Pulmonary Inflammation; Pulmonary Pathology; Recording of previous events; Recovery; Research; Resistance; Respiratory physiology; Techniques; Terminal Bronchiole; Testing; Therapeutic; Time; Toxic effect; Trachea; Trees; Unconscious State; United States; Ventilator; acute symptom; airway obstruction; base; chemical threat; chlorine gas; efficacy testing; injury and repair; interest; lung injury; methacholine; morphometry; novel; prevent; pulmonary function; repaired; research study; respiratory; respiratory health; small airways disease

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.

氯气是一种剧毒呼吸道刺激性，由于 可能在工业事故或恐怖袭击中释放它。氯的急性作用 吸入包括呼吸困难，低氧血症，肺炎和肺水肿。长期后果的后果 氯吸入包括肺功能障碍和结构变化 在某些暴露的个体中观察到。我们的合作者Erik Svendsen博士记录了肺部 由于较大的人群暴露于氯的个体人群中的功能异常 2005年在南卡罗来纳州格兰尼特维尔发生的意外释放。结果指向了一系列呼吸系统 疾病指出，但表明一个重要的组成部分涉及小气道疾病。障碍 为持续性氯诱导的肺部疾病而开发的对策是缺乏相关的动物 效率测试的模型。我们的初步数据表明暴露于氯的兔子并检查了7 几天后 支气管炎闭塞（BO）。这些动物暴露了正常基线肺阻力，但暴露了 对遗传方法的过度反应性。基于这些初步数据，我们建议对这些数据进行扩展 开发一个模型的研究，在该模型中，对小气道的陈述性变化更为广泛，导致了 在增加的基线肺耐药性中，如暴露于氯气的人所观察到的。我们将 然后评估氯暴露后给予潜在对策的效率 预防小气道疾病。要测试的假设是：1）增加暴露后 监测时间和/或氯剂量将产生宽度的小气道BO病变，导致 基线肺阻力显着增加； 2）用遗传性皮质类固醇加ß-治疗 氯暴露后的肾上腺激动剂将抑制BO病变和异常肺的发展 功能。具体目的1将是开发一种持续性氯诱发的肺疾病的动物模型， 复制在氯暴露的人类中观察到的疾病状态。具体目标2将是评估 目前可用的疗法（吸入皮质类固醇加长效β-肾上腺素能激动剂） 持续的氯诱导的肺部疾病。这些探索性研究将产生有价值的信息 旨在开发适当的动物模型进行对策测试，并将生成初始数据 关于目前用于刺激性诱导的哮喘的治疗效率，可以很容易地 被用作对策。