Countermeasures for chlorine-induced airway fibrosis

氯诱发气道纤维化的对策

基本信息

批准号：
8898799
负责人：
Gary W. Hoyle
金额：
$ 40.24万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898799
关键词：
Acute Adrenergic Agonists Affect Agonist Animals Breathing Cell Proliferation Chemical Warfare Chemicals Chlorine Chronic Cyclic AMP Development Disease Dyspnea Epithelial Epithelial Cells Epithelium Exposure to Ferrets Fibrosis Goals Health Human Hypoxemia Iloprost Impairment Individual Industrial Accidents Inflammation Irritants Kinetics Lesion Lithium Lithium Chloride Lung Measurement Modeling Mus Non-Rodent Model Phosphodiesterase Inhibitors Plasminogen Plasminogen Activator Plasminogen Activator Inhibitor 1 Poison Prevention Production Prostaglandins Pulmonary Edema Pulmonary Inflammation Recording of previous events Research Resistance Resolution Respiratory System Respiratory physiology Rodent Rolipram Signal Pathway Signal Transduction Site Structure Structure of respiratory epithelium Symptoms Testing Time Toxic effect Unconscious State United States Urokinase airway epithelium airway hyperresponsiveness airway obstruction animal rule butaprost chemical threat chlorin chlorine gas efficacy testing formoterol inhibitor/antagonist injury and repair lung development lung injury methacholine novel phosphoric diester hydrolase prevent pulmonary function receptor repaired research study respiratory restoration

项目摘要

DESCRIPTION (provided by applicant): 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 pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema, inflammation, airway obstruction, and airway hyperreactivity within one day after exposure. In new studies related to the current application, we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast, portions of airways with few surviving epithelial cells are repaired inefficiently, and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function, including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application, we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function; agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease. Specific Aim 1 will characterize airway epithelial repair, airway fibrosis, and lung function impairment following chlorine exposure in mice. Specific Aims 2-5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost; the long-lasting ss-agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram; stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin; and manipulation of Wnt/ss-catenin signaling with lithium chlorie or pyrvinium. Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.

描述（由申请人提供）：氯气是一种剧毒的呼吸道刺激物，被认为是化学威胁剂，因为它可能在工业事故或恐怖袭击中释放。吸入氯的急性影响包括呼吸困难、低氧血症、肺炎和肺水肿。吸入氯的长期后果包括在一些接触者中观察到的肺功能损害和气道结构变化。我们开发了一种小鼠氯吸入模型，动物在接触氯后一天内出现肺水肿、炎症、气道阻塞和气道高反应性。在与当前应用相关的新研究中，我们描述了吸入氯后较长时间内肺部的损伤和修复。我们观察到，部分上皮损失的气道通过在氯暴露中幸存的上皮细胞的增殖和分化而迅速修复。相比之下，存活上皮细胞很少的气道部分修复效率低下，并且在接触氯后一周内，这些部位会出现纤维增生性病变。气道纤维化的发展与肺功能受损有关，包括呼吸系统阻力增加和气道对吸入乙酰甲胆碱的高反应性。在当前的应用中，我们建议制定可在化学攻击或意外释放后采取的对策，以预防氯引起的气道疾病。在拟议的研究中要检验的假设是，氯性肺损伤后气道上皮的低效修复会导致气道纤维化和肺功能受损。模拟气道上皮抗纤维化作用或刺激气道修复的药物将改善二氢卟酚引起的气道疾病。具体目标 1 将表征气道上皮修复、气道纤维化、小鼠接触氯后肺功能受损。具体目标 2-5 将评估以下潜在对策治疗氯诱发气道疾病的功效：前列腺素受体激动剂布他前列素和伊洛前列素；长效SS激动剂福莫特罗和4型磷酸二酯酶抑制剂咯利普兰；用尿激酶型纤溶酶原激活剂或纤溶酶原激活剂抑制剂-1抑制剂tiplaxtinin刺激纤溶酶原激活；以及用氯化锂或吡维铵操纵 Wnt/ss-catenin 信号传导。具体目标 6 将涉及开发氯诱发气道疾病的雪貂模型，并测试这种非啮齿动物的对策。拟议的研究预计将找到一种预防因急性高水平接触氯而引起的慢性气道疾病的对策。