Novel Therapies for Chlorine-Induced Lung Injury

描述（由申请人提供）：氯气是一种剧毒的呼吸道刺激物，被认为是一种化学威胁剂。本课题的目的是研究氯吸入性肺损伤的医学对策。在之前的U01奖项中，开发了一种氯气吸入小鼠模型，对氯暴露后肺损伤进行了详细的表征，研究了代表治疗干预可能目标的信号通路，测试了操纵感兴趣的信号通路的策略，并确定了显著抑制氯暴露小鼠肺损伤或炎症的化合物。罗利普兰是一种4型磷酸二酯酶抑制剂，可刺激肺泡液运输，减少肺水肿，抑制气道高反应性。雷公藤甲素是一种二萜类抗炎化合物，能抑制氯引起的肺部炎症。在目前的应用中，罗利普兰和雷公藤甲素的配方将用于肌肉注射，这是潜在的大规模伤亡情况的首选递送途径。此外，甲基强的松龙，一种fda批准的抗炎化合物，将被评估为雷公藤甲素的替代品。要测试的总体假设是，静脉注射一种胶囊状的罗利普兰与一种抗炎化合物联合使用，将是治疗氯致肺损伤最有效的对策。对策配方将在小鼠中进行试验，以确定对氯诱导的急性肺损伤的疗效，评估对气道重塑和气道高反应性的长期影响，并测量有效的暴露后治疗窗口的长度。最有效的对策配方将在兔子身上进行评估，以证明在非啮齿动物模型中的有效性。对氯致小鼠和家兔肺损伤有效的优化对策配方将需要进一步的研究，以获得监管部门的批准，包括收集药代动力学/药效学和毒性数据，并使用现行的良好生产规范生产对策。

DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent. The goal of the research proposed in this renewal application is to develop a medical countermeasure to treat lung injury induced by chlorine inhalation. During the previous U01 award, a mouse model of chlorine gas inhalation was developed, a detailed characterization of lung injury following chlorine exposure was performed, signaling pathways representing possible targets for therapeutic intervention were investigated, strategies for manipulating signaling pathways of interest were tested, and compounds that significantly inhibited lung injury or inflammation in chlorine-exposed mice were identified. Rolipram, a type 4 phosphodiesterase inhibitor, was shown to stimulate alveolar fluid transport, decrease pulmonary edema, and inhibit airway hyperreactivity. Triptolide, a diterpenoid anti-inflammatory compound, inhibited chlorine-induced lung inflammation. In the present application, formulations of rolipram and triptolide will be developed for intramuscular (i.m.) injection, a preferred delivery route for potential mass casualty situations. In addition, methylprednisolone, an FDA-approved anti-inflammatory compound, will be evaluated as an alternative to triptolide. The overall hypothesis to be tested is that i.m. injection of an encapsulated formulation of rolipram in combination with an anti-inflammatory compound will represent the most effective countermeasure for chlorine-induced lung injury. Countermeasure formulations will be tested in mice to determine efficacy against chlorine-induced acute lung injury, to assess longer term effects on airway remodeling and airway hyperreactivity, and to measure the length of effective post-exposure treatment window. The most effective countermeasure formulation will be evaluated in rabbits to demonstrate efficacy in a non-rodent animal model. An optimized countermeasure formulation with efficacy against chlorine-induced lung injury in mice and rabbits will be subject to additional studies necessary for progression toward regulatory approval, including collection of pharmacokinetic/pharmacodynamic and toxicity data and production of the countermeasure using current good manufacturing practices. Public Health Relevance: The goal of the proposed experiments is to develop novel ways to treat acute lung injury caused by chlorine gas inhalation. The research will focus on medical countermeasures that can be easily and rapidly administered in a mass casualty situation. 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.