Novel Therapies for Chlorine-Induced Lung Injury

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。本次更新申请中提出的研究目标是开发一种治疗氯气吸入所致肺损伤的药物对策。在之前的U01奖项中，建立了氯气吸入的小鼠模型，对氯气暴露后的肺损伤进行了详细的表征，研究了代表可能的治疗干预目标的信号通路，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气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，被证明可以刺激肺泡液运输，减轻肺水肿，并抑制呼吸道高反应性。雷公藤甲素是一种二萜类抗炎化合物，可抑制氯诱导的肺部炎症。在本申请中，罗利普兰和雷公藤甲素的配方将被开发用于肌肉内(肌注)。注射，对于潜在的大规模伤亡情况是首选的运送途径。此外，FDA批准的抗炎化合物甲基强的松龙将作为雷公藤甲素的替代品进行评估。需要检验的总体假设是，IM。注射罗利普兰胶囊和抗炎化合物将是治疗氯气引起的肺损伤的最有效的对策。将在小鼠身上测试对策配方，以确定对氯诱导的急性肺损伤的疗效，评估对呼吸道重塑和气道高反应性的长期影响，并测量暴露后有效治疗窗口的长度。最有效的对策配方将在兔子身上进行评估，以在非啮齿动物模型中证明有效性。对氯气引起的小鼠和兔肺损伤有效的优化对策配方将需要进行额外的研究，以期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，并利用当前良好的生产实践生产对策。 公共卫生相关性：拟议实验的目标是开发治疗氯气吸入引起的急性肺损伤的新方法。这项研究将集中于在大规模伤亡情况下可以轻松、快速地实施的医疗对策。这类研究之所以重要，是因为担心美国平民可能会因意外或故意释放剧毒化学品而受到不利影响。

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.