Inhibition of soluble epoxide hydrolase protects against phosgene-induced lung injuries

抑制可溶性环氧化物水解酶可预防光气引起的肺损伤

基本信息

批准号：
10207055
负责人：
Satyanarayana Achanta
金额：
$ 24.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207055
关键词：
Acids Acute Lung Injury Albumins Alveolar American Angiotensin II Anti-Inflammatory Agents Antidotes Asphyxia Asthma Attenuated Bleomycin Blood capillaries Bone Diseases Bronchitis Bronchoalveolar Lavage Fluid Bronchoconstriction Cardiovascular Diseases Chemical Injury Chemical Weapons Chemicals Chlorides Chronic Chronic Obstructive Airway Disease Clinical Trials Development Disease Disease model Docosahexaenoic Acids Dose Drug Kinetics Dyes Eicosanoids Eicosapentaenoic Acid Enzymes Epoxide hydrolase Epoxy Compounds Fatty Acids Functional disorder Future Gases Goals Histopathology Hour Human Hyperoxia Industrial Accidents Inflammation Inflammatory Inflammatory Response Inhalation Injury Intramuscular Late Effects Lead Lipid Peroxidation Lipopolysaccharides Literature Lung Lung Inflammation Lung diseases Mechanics Mediating Membrane Modeling Morbidity - disease rate Mus Neurodegenerative Disorders Omega-3 Fatty Acids Outcome Pain Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phosgene Plasma Property Proteins Pulmonary Edema Pulmonary Fibrosis Recovery Regimen Rodent Model Rubber Sepsis Smoke Structure of parenchyma of lung Survival Rate Terrorism Testing Therapeutic Therapeutic Effect Transportation Treatment Efficacy White Blood Cell Count procedure Work World War I arachidonate base cohort cytokine drug candidate effective therapy efficacy testing humane endpoint improved in vivo inhibitor/antagonist injured intraperitoneal liquid chromatography mass spectrometry lung injury medical countermeasure methacholine mortality mouse model primary endpoint receptor screening secondary endpoint severe injury side effect standard of care symptom treatment targeted treatment therapeutic evaluation therapeutic lead compound therapeutic target vascular injury weapons

项目摘要

Summary Phosgene gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. Soluble epoxide hydrolase (sEH) enzyme mediates the degradation of beneficial epoxyeicosatrienoic acids (EETs) and other fatty acid epoxides such as ω-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) that mediate anti-inflammatory pathways and stimulate pro-resolving mechanisms. sEH enzyme levels and its downstream products have significantly increased in pulmonary disease models. Phosgene gas causes lipid peroxidation and membrane disruption that leads to alveolar-capillary barrier dysfunction. Soluble epoxide hydrolase inhibitors (sEHI) mitigated lipopolysaccharide (LPS), hyperoxia, and angiotensin II-induced acute lung injury (ALI). Further, sEHI also ameliorated chronic obstructive pulmonary disease (COPD), asthma, bleomycin-induced pulmonary fibrosis, and smoke-induced chronic lung injuries. In addition to pulmonary indications, sEHIs have shown beneficial therapeutic benefits in inflammatory diseases, destructive bone diseases, sepsis, cardiovascular diseases, neurodegenerative diseases, and pain. Some of the sEHI have been tested in clinical trials with encouraging outcomes and no potential side effects. While the therapeutic effects of sEHIs hold great promise as a broad-spectrum treatment candidate, these inhibitors have not yet been tested in pulmonary chemical injuries. In this application, we hypothesize that inhibiting soluble epoxide hydrolase ameliorates phosgene gas-induced lung injury, leading to decreased morbidity and improved recovery. Here, we propose to test the efficacy of three highly potent and selective sEHIs in mouse models of phosgene inhalation injury, with the goal to identify a lead therapeutic drug candidate as a future human medical countermeasure. The following aims are proposed: Aim 1: Assess the therapeutic effects of sEH inhibitors in a mouse model of phosgene gas-induced acute lung injury; Aim 2: Determine the pharmacokinetic profile of the most potent sEH inhibitor in naïve and phosgene gas-exposed mice; Aim 3: Assess the therapeutic efficacy of most potent sEH inhibitor in reducing mortality in a mouse model of phosgene gas-induced lung injury.

概括光气在战争中被用作恐怖武器，并导致许多美国人受伤尽管交通事故或工业事故造成了破坏性影响，但还没有基于机制的治疗方法。开发出可溶性环氧化物水解酶（sEH），可介导有益的环氧二十碳三烯酸的降解。酸 (EET) 和其他脂肪酸环氧化物，例如 ω-3 二十二碳六烯酸 (DHA) 和二十碳五烯酸 (EPA) 介导抗炎途径并刺激促消退机制。肺部疾病中sEH酶水平及其下游产物显着升高光气气体导致脂质过氧化和膜破坏，从而导致肺泡毛细血管损伤。可溶性环氧化物水解酶抑制剂（sEHI）减轻脂多糖（LPS），高氧血症和血管紧张素 II 诱导的急性肺损伤 (ALI) 此外，sEHI 还可以改善慢性肺损伤。阻塞性肺病 (COPD)、哮喘、博来霉素诱发的肺纤维化和烟雾诱发的肺纤维化除了肺部适应症外，sEHI 还显示出有益的治疗效果。炎症性疾病、破坏性骨病、败血症、心血管疾病、神经退行性疾病一些 sEHI 已经在临床试验中进行了测试，取得了令人鼓舞的结果，但没有任何结果。虽然 sEHI 的治疗效果作为一种广谱治疗具有广阔的前景。候选者中，这些抑制剂尚未在肺部化学损伤中进行测试。其次，抑制可溶性环氧化物水解酶可改善光气引起的肺损伤，从而导致降低发病率并提高康复率。在这里，我们建议在小鼠模型中测试三种高效、选择性 sEHI 的功效光气吸入性损伤，目标是确定一种主要的治疗药物候选物作为未来的人类医学提出以下对策：目标 1：评估 sEH 抑制剂的治疗效果。光气引起的急性肺损伤的小鼠模型；目标 2：确定该药物的药代动力学特征。对首次接触光气的小鼠最有效的 sEH 抑制剂；目标 3：评估 sEH 的治疗效果；是降低光气所致肺损伤小鼠模型死亡率的最有效的 sEH 抑制剂。