Novel Therapies for Chlorine-Induced Lung Injury

氯引起的肺损伤的新疗法

基本信息

批准号：
8144562
负责人：
Gary W. Hoyle
金额：
$ 57.74万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-29 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144562
关键词：
Acute Lung Injury Affect Alveolar Animal Model Anti-Inflammatory Agents Anti-inflammatory Award Breathing Chemicals Chlorine Collection Data Development Diterpenes Drug Formulations Drug Kinetics Encapsulated FDA approved Gases Goals Human Inflammation Intramuscular Injections Irritants Length Liquid substance Long-Term Effects Lung Inflammation Maximum Tolerated Dose Measures Medical Methylprednisolone Mus No-Observed-Adverse-Effect Level Oryctolagus cuniculus Pathway interactions Pharmacodynamics Phosphodiesterase Inhibitors Poison Principal Investigator Production Pulmonary Edema Research Research Institute Rodent Rolipram Route Signal Pathway Testing Therapeutic Intervention Toxic effect Universities airway hyperresponsiveness airway remodeling chemokine chlorine gas efficacy testing interest lung injury mouse model neutrophil novel pre-clinical prevent public health relevance research study respiratory triptolide

项目摘要

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.

描述（由申请人提供）：氯气是一种剧毒的呼吸道刺激物，被认为是化学威胁剂。本次更新申请中提出的研究目标是开发一种医疗对策来治疗吸入氯引起的肺损伤。在上一届 U01 奖项期间，开发了氯气吸入小鼠模型，对氯暴露后肺损伤进行了详细表征，研究了代表治疗干预可能目标的信号通路，测试了操纵感兴趣信号通路的策略，并鉴定出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，可刺激肺泡液转运、减少肺水肿并抑制气道高反应性。雷公藤甲素是一种二萜类抗炎化合物，可抑制氯引起的肺部炎症。在本申请中，咯利普兰和雷公藤甲素的制剂将被开发用于肌内（i.m.）注射，这是潜在的大规模伤亡情况的优选递送途径。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。要测试的总体假设是 i.m.注射咯利普兰胶囊制剂与抗炎化合物的组合将是针对氯引起的肺损伤的最有效对策。对策制剂将在小鼠中进行测试，以确定针对氯引起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，并测量有效暴露后治疗窗口的长度。最有效的对策配方将在兔子中进行评估，以证明在非啮齿动物模型中的功效。对小鼠和兔子中氯引起的肺损伤有效的优化对策配方将接受必要的额外研究，以取得监管批准，包括收集药代动力学/药效和毒性数据以及使用当前良好生产规范生产对策。公共健康相关性：拟议实验的目标是开发治疗因吸入氯气引起的急性肺损伤的新方法。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。此类研究很重要，因为人们担心美国平民可能会因剧毒化学品的意外或故意释放而受到不利影响。