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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.

总结