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

• 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
• 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

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 Phosgene Gas在战争中被用作恐怖武器，并伤害了许多美国人 运输或工业事故。尽管有毁灭性的影响，但没有基于机制的治疗 发达。可溶性环化水酶（SEH）酶介导有益的环氧树叶酸酯的降解 酸（EET）和其他脂肪酸环氧化物，例如ω-3 docosahexaenoic（DHA）和eicosapentaenoic酸 （EPA）介导抗炎途径并刺激促进机制。 SEH酶水平及其下游产品在肺部疾病中显着增加 型号。磷光气体会导致脂质过氧化和膜破坏，从而导致肺泡毛细血管 障碍障碍。可溶性环氧水解酶抑制剂（SEHI）减轻脂多糖（LPS）， 高氧和血管紧张素II诱导的急性肺损伤（ALI）。此外，SEHI还改善了慢性 阻塞性肺疾病（COPD），哮喘，博来霉素诱导的肺纤维化以及烟雾诱导的 慢性肺部受伤。除了肺部适应症外，Sehis还显示出有益的治疗益处 在炎症性疾病，破坏性骨骼疾病，败血症，心血管疾病，神经退行性 疾病和痛苦。一些SEHI已在临床试验中进行了测试，令人鼓舞，没有 潜在的副作用。虽然Sehis的治疗作用具有广阔的良好治疗 候选人，这些抑制剂尚未在肺化学损伤中进行测试。在此应用程序中，我们 假设抑制固体环氧化物水解酶可以改善磷气体诱导的肺损伤，导致 降低发病率并改善恢复。 在这里，我们建议在小鼠模型中测试三个高潜力和选择性SEHI的效率 Phosgene吸入损伤，目的是将铅疗法候选药物识别为未来的人类医学 对策。提出了以下目的：目标1：评估A中SEH抑制剂的治疗作用 磷气体诱导的急性肺损伤的小鼠模型；目标2：确定药代动力学特征 在幼稚和磷气体暴露的小鼠中，最有效的SEH抑制剂；目标3：评估治疗效率 在磷气体诱导的肺损伤的小鼠模型中，最有效的SEH抑制剂可降低死亡率。