Countermeasures for chlorine-induced airway fibrosis

描述（由申请人提供）：氯气是一种剧毒呼吸道刺激物，由于其可能在工业事故或恐怖袭击中释放，因此被视为化学威胁剂。吸入氯气的急性效应包括呼吸困难、低氧血症、肺炎和肺水肿。吸入氯的长期后果包括肺功能损害和气道结构变化，这在一些接触者中已经观察到。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发生肺水肿、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肺损伤和修复的特征。我们已经观察到，部分上皮损失的气道通过在氯暴露中存活的上皮细胞的增殖和分化而快速修复。与此相反，部分气道与几个幸存的上皮细胞修复效率低下，和纤维增生性病变发展在这些网站氯暴露后一周内。这种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。在本申请中，我们提出开发可以在化学攻击或意外释放后施用的对策，以预防氯诱导的气道疾病。在所提出的研究中待检验的假设是，氯肺损伤后气道上皮的低效修复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氯诱导的气道疾病。具体目标1将表征气道上皮修复、气道纤维化， 和肺功能损害。具体目标2-5将评价以下潜在对策治疗氯诱导的气道疾病的疗效：前列腺素受体激动剂布他前列素和伊洛前列素;长效β-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抑制剂替普拉替宁刺激纤溶酶原激活;以及用氯化锂或吡咯烷鎓操纵Wnt/β-连环蛋白信号传导。具体目标6将涉及氯诱导的呼吸道疾病的雪貂模型的发展和测试的对策，在这个非啮齿类动物物种。预计拟议的研究将确定预防慢性气道疾病的对策，这种疾病是由于急性高水平接触氯而引起的。

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.