Lipoxins in Severe Asthma (LIPSA)

描述（由申请人提供）：严重哮喘影响5-10%的哮喘患者，并与生活质量差、发病率高和与哮喘相关的不成比例的经济成本份额相关。它的特点是持续气道炎症，尽管皮质类固醇治疗。脂毒素和15-epi-脂毒素是一类内源性小分子，在肺部产生，并下调严重哮喘炎症的炎症反应特征。一些患有严重哮喘的个体在脂质生成方面存在缺陷，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造成的。最近，抑制可溶性环氧化物水解酶被证明可以增加肺炎症中脂毒素和15-外延脂毒素的产生。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（EETs）转化为相应的二羟基形式。可溶性环氧化物水解酶的抑制导致eet的相对增加和花生四烯酸代谢的转变，从而增加其酶促转化为脂素和15-外延脂素。可溶性环氧化物水解酶的有效抑制剂目前正处于临床开发阶段，包括一项用于动脉粥样硬化的II期试验。综上所述，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哮喘的有益作用，但这尚未得到直接证实。提出的实验将验证可溶性环氧化物脂肪酶的抑制将增加严重哮喘中脂素的产生的假设。在CADET I中，我们建议利用来自严重哮喘患者的血液和支气管肺泡灌洗液样本进行两个特定目的：}}验证可溶性环氧化物水解酶抑制作为哮喘炎症中增加脂素生成的治疗靶点；}}开发一种非侵入性方法来识别气道脂素水平低的严重哮喘受试者亚群。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对类固醇抵抗性严重哮喘和低脂素生成受试者的益处。相关性（见说明书）：严重哮喘患者对抗炎控制疗法（包括皮质类固醇）无反应，因此发病率过高，更需要医疗保健支持。在本提案中，我们将利用一项由90名严重哮喘患者资助的多中心临床试验收集的样本来(1)验证可溶性环氧化物水解酶抑制作为潜在的新治疗靶点；(2)开发一种非侵入性方法来识别最有可能从这种治疗中受益的严重哮喘患者。

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.