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

摘要 光气已被用作恐怖分子的武器，在战争中，并已在 交通或工业事故。尽管它有毁灭性的影响，但还没有任何基于机制的治疗方法 发展起来的。可溶性环氧化物水解酶介导有益环氧二十碳三烯酸的降解 酸(EET)和其他脂肪酸环氧化物，如ω-3二十二碳六烯酸和二十碳五烯酸 (EPA)调节抗炎途径并刺激促分解机制。 肺部疾病中SEH酶水平及其下游产物显著增加 模特们。光气引起脂质过氧化和膜破坏，导致肺泡毛细血管 屏障功能障碍。可溶性环氧化物水解酶抑制剂(SEHI)可减轻脂多糖(LPS)， 高氧血症和血管紧张素II诱导的急性肺损伤(ALI)。此外，sEHI还改善了慢性 阻塞性肺疾病(COPD)、哮喘、博莱霉素诱导的肺纤维化和烟雾诱导 慢性肺损伤。除了肺部适应症外，sEHIs还显示出有益的治疗效果。 在炎症性疾病、破坏性骨病、败血症、心血管疾病、神经退行性疾病中 疾病和痛苦。一些sEHI已经在临床试验中进行了测试，结果令人鼓舞，但没有 潜在的副作用。虽然sEHIs的治疗效果作为一种广谱治疗有着很大的前景 候选，这些抑制剂还没有在肺化学损伤中进行测试。在此应用程序中，我们 假设抑制可溶性环氧化物水解酶可减轻光气诱导的肺损伤，导致 以减少发病率和改善康复。 在这里，我们建议测试三种高度有效和选择性的sEHIs在小鼠模型中的疗效 光气吸入性损伤，目标是确定一种主要的候选治疗药物作为未来的人类医学 对策。提出了以下目标：目标1：评估sEH抑制剂的治疗效果。 光气致小鼠急性肺损伤模型的建立；目的2：测定小鼠肺泡灌洗液的药代动力学 在幼稚和光气暴露的小鼠中最有效的sEH抑制剂；目标3：评估 最有效的sEH抑制剂在降低光气诱导的肺损伤小鼠模型中的死亡率。

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.