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）：严重哮喘影响5-10%的哮喘患者，并且与生活质量差、发病率过高以及与哮喘相关的经济成本比例过高有关。其特征是持续气道炎症，尽管皮质类固醇治疗。脂氧素和15-表-脂氧素是一类内源性小分子，其在肺中产生并下调严重哮喘中炎症特征性的炎症反应。一些患有严重哮喘的个体在脂氧素的产生方面存在缺陷，因此这些个体的过度炎症可能是由于这些保护性介质的产生减少。最近，可溶性氧化物水解酶的抑制被证明在肺部炎症中增加脂氧素和15-表-脂氧素的产生。可溶性环氧化物水解酶将花生四烯酸衍生的环氧二十碳三烯酸（E3）转化为它们相应的二羟基形式。可溶性环氧化物水解酶的抑制导致雌二醇的相对增加和花生四烯酸代谢的转变，这增加了花生四烯酸向脂氧素和15-表-脂氧素的酶促转化。可溶性环氧化物水解酶的有效抑制剂目前正在临床开发中，包括动脉粥样硬化的II期试验。总之，在小鼠和人类模型系统中有多条证据支持可溶性环氧化物水解酶抑制剂在哮喘中的有益作用，但尚未直接确立。所提出的实验将检验抑制可溶性环氧化物水解酶将增加严重哮喘中脂氧素生成的假设。 在CADET I中，我们提出利用来自患有严重哮喘的个体的血液和支气管肺泡灌洗液的样品用于两个特定目的：}}将可溶性环氧化物水解酶抑制作为治疗靶点以增加哮喘炎症中脂氧素的产生，和}}开发非侵入性方法以鉴定具有低气道脂氧素水平的严重哮喘受试者的亚群。 拟议的实验将为CADET II的临床试验奠定基础，该试验将测试可溶性环氧化物水解酶抑制剂在类固醇抵抗性严重哮喘和低脂氧素生成受试者中的益处。相关性（见说明）：重度哮喘患者对抗炎控制剂治疗（包括皮质类固醇）无反应，因此发病率过高，更需要医疗支持。在本提案中，我们将利用在90名重度哮喘受试者的资助、多中心临床试验中收集的样本，（1）验证可溶性环氧化物水解酶抑制作为潜在的新型治疗靶点，（2）开发一种非侵入性方法，以鉴定最有可能从该治疗中获益的重度哮喘患者。