Novel Therapies for Chlorine-Induced Lung Injury

描述（由申请人提供）：氯气是一种高毒性呼吸道刺激物，被认为是一种化学威胁剂。本更新申请中提出的研究目标是开发一种治疗氯吸入性肺损伤的医学对策。在之前的U01奖项中，开发了氯气吸入的小鼠模型，进行了氯暴露后肺损伤的详细表征，研究了代表治疗干预的可能靶点的信号通路，测试了操纵感兴趣的信号通路的策略，并确定了显着抑制氯暴露小鼠肺损伤或炎症的化合物。咯利普兰是一种4型磷酸二酯酶抑制剂，可刺激肺泡液体转运，减轻肺水肿，抑制气道高反应性。雷公藤内酯醇，一种二萜类抗炎化合物，抑制氯诱导的肺部炎症。在本申请中，将开发咯利普兰和雷公藤内酯醇的制剂用于肌内（i. m.）注射是潜在大规模伤亡情况下的首选输送途径。此外，甲基强的松龙，FDA批准的抗炎化合物，将作为雷公藤内酯醇的替代品进行评估。待检验的总体假设是，注射咯利普兰的包封制剂与抗炎化合物的组合将代表氯诱导的肺损伤的最有效对策。将在小鼠中测试对策制剂，以确定针对氯诱导的急性肺损伤的功效，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。将在家兔中评价最有效的对策制剂，以证明在非啮齿动物模型中的有效性。对小鼠和家兔中氯诱导肺损伤有效的优化对策制剂将进行必要的额外研究，以获得监管批准，包括收集药代动力学/药效学和毒性数据以及使用当前良好生产规范生产对策。 公共卫生相关性：拟议实验的目标是开发新的方法来治疗氯气吸入引起的急性肺损伤。该研究将重点关注在大规模伤亡情况下可以轻松快速实施的医疗对策。这种类型的研究很重要，因为人们担心美国平民可能会受到意外或故意释放剧毒化学品的不利影响。

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.