Novel Therapies for Chlorine-Induced Lung Injury

氯引起的肺损伤的新疗法

• 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
• 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

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）：氯气是一种被认为是化学威胁剂的剧毒呼吸刺激性。在此更新应用中提出的研究的目的是开发一种医学对策，以治疗氯吸入引起的肺损伤。在先前的U01奖中，开发了氯气吸入的小鼠模型，进行了氯暴露后的肺损伤的详细表征，研究了信号传导途径，该途径研究了治疗干预的可能目标，测试了感兴趣的信号途径的策略，并测试了感兴趣的信号通路，并显着识别了肺部受伤的化合物。 Rolipram是一种4型磷酸二酯酶抑制剂，已显示可刺激肺泡液的转运，减少肺水肿并抑制气道过度反应性。 triptolide是二萜抗炎化合物，抑制了氯诱导的肺部炎症。在本应用中，将开发Rolipram和Triptolide的制剂用于肌肉内（I.M.）注射，这是潜在的质量伤亡情况的首选分娩途径。此外，将评估由FDA批准的抗炎化合物甲基强酮作为triptolide的替代品评估。要测试的总体假设是I.M.注射胶片的封装配方与抗炎化合物结合使用将代表氯诱导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，以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中评估，以证明在非塑性动物模型中的功效。针对氯诱导的小鼠和兔子的肺损伤具有功效的优化对策制剂将受到向调节性批准进展所需的其他研究，包括收集药代动力学/药效学和毒性数据，并使用当前良好的制造实践来收集对策。 公共卫生相关性：拟议的实验的目的是开发新的方法来治疗氯气吸入引起的急性肺损伤。这项研究将重点放在可以在大规模伤亡情况下轻松，迅速管理的医学对策。这种类型的研究很重要，因为担心美国平民可能会受到意外或故意释放有毒化学物质的不利影响。