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

总结 在战争中，光气被用作恐怖主义武器， 交通或工业事故。尽管其破坏性的影响，没有机制为基础的治疗一直是 开发可溶性环氧化物水解酶（sEH）介导有益的环氧二十碳三烯酸的降解 脂肪酸（Escherichia coli）和其它脂肪酸环氧化物，例如ω-3二十二碳六烯酸（DHA）和二十碳五烯酸（Escherichia coli）。 (EPA)介导抗炎途径并刺激促消退机制。 sEH酶水平及其下游产物在肺部疾病中显著增加 模型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）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、博莱霉素诱导的肺纤维化和吸烟诱导的肺纤维化 慢性肺损伤除了肺部适应症外，sEHI还显示出有益的治疗益处 炎症性疾病、破坏性骨疾病、败血症、心血管疾病、神经退行性疾病 疾病和疼痛。一些sEHI已经在临床试验中进行了测试，结果令人鼓舞， 潜在的副作用虽然sEHI的治疗效果作为广谱治疗具有很大的希望， 候选人，这些抑制剂尚未在肺部化学损伤中进行测试。在本申请中，我们 假设抑制可溶性环氧化物水解酶可改善光气气体诱导的肺损伤， 降低发病率和改善恢复。 在这里，我们建议在小鼠模型中测试三种高效和选择性sEHI的功效。 光气吸入性损伤，目标是确定一种领先的治疗药物候选人作为未来的人类医疗 对策提出了以下目的：目的1：评估sEH抑制剂在慢性炎症中的治疗效果。 目的2：确定光气气体诱导的急性肺损伤小鼠模型的药代动力学特征 在未处理和暴露于光气气体的小鼠中最有效的sEH抑制剂;目的3：评估的治疗效果 最有效的sEH抑制剂在降低小鼠模型的光气气体诱导的肺损伤的死亡率。

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.