Countermeasures for chlorine-induced airway fibrosis

氯诱发气道纤维化的对策

基本信息

批准号：
8550807
负责人：
Gary W. Hoyle
金额：
$ 37.83万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550807
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 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 Pneumonia Poison Prevention Production Prostaglandins Pulmonary Edema 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 chlorin chlorine gas efficacy testing formoterol inhibitor/antagonist injury and repair lung development lung injury methacholine novel phosphoric diester hydrolase prevent prostaglandin EP2 receptor public health relevance 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）：氯气是一种高毒的呼吸刺激性，被认为是化学威胁剂，因为它可能会在工业事故或恐怖袭击中释放。氯吸入的急性作用包括呼吸困难，低氧血症，肺炎和肺水肿。氯吸入的长期后果包括在某些暴露的个体中观察到的肺功能障碍和气道结构变化。我们已经开发了一种小鼠氯吸入模型，其中动物在暴露后一天内会发展肺水肿，炎症，气道阻塞和气道高反应性。在与当前应用有关的新研究中，我们在氯气吸入后更长的时间对肺的损伤和修复进行了表征。我们已经观察到，上皮部分损失的气道通过在氯暴露的上皮细胞的增殖和分化迅速修复。相比之下，部分存活的上皮细胞的气道效率低下，并且在氯暴露后一周内在此类部位发展纤维增生性病变。气道纤维化的这种发展与肺功能受损有关，包括增加呼吸系统耐药性和气道对吸入甲基酸的高反应性。在当前的应用中，我们建议开发对对策，这些对策可以在化学攻击或意外释放后进行给药，以防止氯引起的气道疾病。在拟议的研究中要检验的假设是，氯肺损伤后气道上皮的效率低下会导致气道纤维化和肺功能受损。模仿气道上皮或刺激气道修复的抗纤维化作用的药物会改善氯素诱导的气道疾病。特定的目标1将表征气道上皮修复，气道纤维化，小鼠氯暴露后的肺功能障碍。具体目的2-5将评估以下潜在对策治疗氯诱导的气道疾病的功效：前列腺素受体激动剂丁克罗斯特和伊洛普洛斯特；持久的SS振动型甲他醇和4型磷酸二酯酶抑制剂Rolipram；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；用氯氯或p基因操纵Wnt/ss-catenin信号传导。具体目标6将涉及开发氯诱导的气道疾病的雪貂模型，并在这种非腐蚀物种中测试对策。拟议的研究预计将确定预防由于急性高水平暴露于氯的导致慢性气道疾病的对策。