Lipoxins in Severe Asthma (LIPSA)

严重哮喘中的脂氧素 (LIPSA)

• 批准号: 8263755
• 负责人: Elliot Israel
• 金额: $ 53.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263755
• 关键词: Acids; Adrenal Cortex Hormones; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Asthma; Atherosclerosis; Biological; Biological Assay; Biological Markers; Biological Models; Blood; Blood specimen; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cells; Characteristics; Clinical; Clinical Trials; Defect; Development; Diagnostic; Dose; Eicosanoids; Enzymes; Epoxide hydrolase; Epoxy Compounds; Exhalation; Fatty Acids; Funding; Generations; Goals; Healthcare; Human; Hydrolase; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhibitory Concentration 50; Lead; Leukotrienes; Lipoxins; Lung; Lung Inflammation; Lung diseases; Measures; Mediating; Mediator of activation protein; Membrane; Metabolism; Methods; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; New Agents; Outcome; Patient Education; Patients; Pharmacodynamics; Phase; Phase II Clinical Trials; Plasma; Play; Population; Preclinical Testing; Principal Investigator; Probability; Process; Production; Quality of life; Reagent; Relative (related person); Research; Role; Sampling; Screening procedure; Severities; Sputum; Staging; Steroid Resistance; System; Techniques; Testing; Therapeutic; Tissues; Urine; Validation; Whole Blood; Work; airway inflammation; arachidonate; asthmatic airway; base; design; economic cost; experience; human disease; inhibitor/antagonist; lipid mediator; lipoxin A4; member; new therapeutic target; novel diagnostics; novel therapeutics; patient population; programs; research clinical testing; research study; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Severe asthma affects 5-10% of asthmatics and is associated with a poor quality of life, excess morbidity and a disproportionate share of the economic costs related to asthma. It is characterized by persistent airway inflammation despite corticosteroid therapy. Lipoxins and 15-epi-lipoxins are a class of endogenous small molecules that are produced in the lung and downregulate inflammatory responses characteristic of the inflammation in severe asthma. Some individuals with severe asthma carry a defect in the generation of lipoxins, so excess inflammation in these individuals may result from decreased production of these protective mediators. Recently, inhibition of soluble expoxide hydrolase was demonstrated to increase production of lipoxins and 15-epi-lipoxins in lung inflammation. Soluble epoxide hydrolase converts arachidonic acid-derived epoxyeicosatrienoic acids (EETs) to their corresponding dihydroxy forms. Inhibition of soluble epoxide hydrolase leads to a relative increase in EETs and a shift in arachidonic acid metabolism that increases its enzymatic conversion to lipoxins and 15-epi-lipoxins. Potent inhibitors of soluble epoxide hydrolase are currently in clinical development, including a phase II trial for atherosclerosis. Taken together, there are multiple lines of evidence in murine and human model systems that would support a beneficial action for soluble epoxide hydrolase inhibition in asthma, but this has not been directly established. The proposed experiments will test the hypothesis that inhibition of soluble epoxide liydrolase will increase lipoxin generation in severe asthma. In CADET I, we propose to utilize samples of blood and bronchoalveolar lavage fluid from individuals with severe asthma for two specific aims to: }} Validate soluble epoxide hydrolase inhibition as a therapeutic target to increase lipoxin generation in asthmatic inflammation, and }} Develop a non-invasive method to identify the sub-population of severe asthma subjects that have low airway levels of lipoxins. The proposed experiments will set the stage for a clinical trial in CADET II that will test the benefits of a soluble epoxide hydrolase inhibitor in subjects with steroid resistant severe asthma and low lipoxin generation. RELEVANCE (See Instructions): Patients with severe asthma do not respond to anti-inflammatory controller therapy, including corticosteroids, and thus experience excess morbidity and a greater need for healthcare support. In this proposal, we will utilize samples collected in a funded, multicenter clinical trial of ninety subjects with severe asthma to (1) validate soluble epoxide hydrolase inhibition as a potential novel therapeutic target and (2) develop a non}} invasive method to identify individuals with severe asthma that are most likely to benefit from this therapy.

描述（由申请人提供）：严重的哮喘影响5-10％的哮喘患者，与生活质量差，发病率过高以及与哮喘相关的经济成本的份额不成比例。尽管皮质类固醇治疗，但其特征是持续的气道炎症。脂毒素和15-EPI脂蛋白是一类内源性小分子，在肺部产生并下调严重哮喘的炎症特征。一些患有严重哮喘的人会导致脂毒素产生缺陷，因此这些个体的过量炎症可能是由于这些保护介质的产生降低而导致的。最近，证明抑制可溶性毒素水解酶可以增加肺部炎症中脂毒素和15-EPI脂蛋白的产生。可溶性环氧化物水解酶将蛛网膜酸衍生的环氧气酸（EET）转化为相应的二羟基形式。抑制可溶性环氧化物水解酶会导致EET相对增加和蛛网膜酸代谢的转移，从而增加了其酶促转化为脂蛋白和15-EPI脂蛋白。可溶性环氧水解酶的有效抑制剂目前正在临床发育中，包括针对动脉粥样硬化的II期试验。综上所述，在鼠和人类模型系统中有多种证据，这些证据将支持哮喘中可溶性环氧化物水解酶抑制的有益作用，但尚未直接确定。提出的实验将检验以下假设：抑制可溶性环氧化物二元酶将增加严重哮喘中的脂蛋白产生。 In CADET I, we propose to utilize samples of blood and bronchoalveolar lavage fluid from individuals with severe asthma for two specific aims to: }} Validate soluble epoxide hydrolase inhibition as a therapeutic target to increase lipoxin generation in asthmatic inflammation, and }} Develop a non-invasive method to identify the sub-population of severe asthma subjects that have low airway levels of脂毒素。 提出的实验将为Cadet II中的临床试验奠定基础，该试验将测试可溶性环氧水解酶抑制剂在类固醇耐药性严重哮喘和低脂氧蛋白产生的受试者中的益处。相关性（请参阅说明）：严重哮喘患者对包括皮质类固醇在内的抗炎控制剂治疗没有反应，因此经历了过量的发病率和更大的医疗保健支持需求。在此提案中，我们将利用在一项资助的，多中心临床试验中收集的样品，该试验对患有严重哮喘的90名受试者（1）验证可溶性环氧化物水解酶抑制作用作为一种潜在的新型治疗靶标，（2）}}}}}}} i侵入性的方法来鉴定患有严重的哮喘患者，这些人最可能受益于这种治疗。