Countermeasures for chlorine-induced airway fibrosis

描述（由申请人提供）：氯气是一种剧毒的呼吸刺激物，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。氯吸入的急性反应包括呼吸困难、低氧血症、肺炎和肺水肿。氯吸入的长期后果包括在一些接触者中观察到的肺功能损害和气道结构改变。我们建立了小鼠氯吸入模型，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，我们已经描述了氯吸入后肺损伤和修复的时间更长。我们已经观察到，部分上皮细胞丢失的气道可以通过在氯暴露中存活的上皮细胞的增殖和分化迅速修复。与此相反，部分存活上皮细胞较少的气道修复效率低下，在接触氯后一周内，这些部位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甲胆碱的高反应性。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进行管理的对策，以防止氯引起的气道疾病。所提出的研究需要验证的假设是，氯肺损伤后气道上皮修复效率低下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可改善氯诱导的气道疾病。特异性Aim 1将表征气道上皮修复，气道纤维化，

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. PUBLIC HEALTH RELEVANCE: The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.