Countermeasures for chlorine-induced airway fibrosis

说明(申请人提供)：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，因为它可能在工业事故或恐怖袭击中释放出来。氯气吸入的急性影响包括呼吸困难、低氧血症、肺炎和肺水肿。氯气吸入的长期后果包括在一些接触氯气的个人中观察到的肺功能损害和呼吸道结构变化。我们已经建立了一种小鼠氯吸入模型，在该模型中，动物在暴露后一天内出现肺水肿、炎症、呼吸道阻塞和呼吸道高反应性。在与当前应用相关的新研究中，我们描述了氯气吸入后较长时间内肺损伤和修复的特征。我们观察到，在氯暴露下存活下来的上皮细胞的增殖和分化可以迅速修复部分上皮细胞丢失的呼吸道。相比之下，呼吸道上皮细胞很少的部分修复效率低下，在氯暴露后一周内，这些部位就会出现纤维增生性病变。这种呼吸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对吸入乙酰甲胆碱的呼吸道高反应性。在目前的应用中，我们建议开发可以在化学攻击或意外释放后使用的对策，以预防氯气引起的呼吸道疾病。在拟议的研究中要检验的假设是，氯肺损伤后呼吸道上皮的低效修复会导致气道纤维化和肺功能受损；模仿气道上皮的抗纤维化作用或刺激气道修复的药物将改善氯气诱导的呼吸道疾病。具体目标1将描述呼吸道上皮修复、气道纤维化、 以及氯气暴露对小鼠肺功能的损害。特定的AIMS 2-5将评估下列潜在对策治疗氯诱导的呼吸道疾病的有效性：前列腺素受体激动剂丁前列酮和伊洛前列酮；长效SS激动剂福莫特罗和4型磷酸二酯酶抑制剂罗利普兰；用尿激酶型纤溶酶原激活剂或纤溶酶原激活物抑制物-1抑制剂替普拉西林刺激纤溶酶原激活；以及用氯化锂或吡喃操纵Wnt/ss-catenin信号转导。具体目标6将涉及建立氯气引起的呼吸道疾病的雪貂模型，并在这种非啮齿动物物种中测试对策。拟议的研究预计将确定预防由于急性高水平接触氯而导致的慢性呼吸道疾病的对策。

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.