AMSA: ALXR/FBR Mediated Signaling in Severe Asthma

描述(申请人提供)：拟议的实验将测试ALX轴失调是持续性哮喘和呼吸道炎症的基础的假设，尽管在一组严重哮喘患者中使用了皮质类固醇治疗。脂氧素A4(LXA4)是一种抗炎和促分解介质，可以与特定的受体(即ALX/FPR2)相互作用，在模型系统中抑制过敏性呼吸道炎症和高反应性。重症哮喘的特征是LXA4降低，这表明这种情况可能源于反向调节的缺陷。ALX/FPR2受体还有另外三个配体，即15-epmer-LXA4、Annexin A1和血清淀粉样蛋白A。所有这四个ALX/FPR2配体都是在哮喘中产生的，与ALX/FPR2受体一起构成了ALX轴。值得注意的是，这两种蛋白配体都可以在体外被皮质类固醇诱导，皮质类固醇是最常见的哮喘控制疗法，与其他三种配体不同，血清淀粉样蛋白a与ALX/FPR2的相互作用矛盾地促进炎症，增加了一组严重哮喘患者可能遭受损害而不是受益于皮质类固醇的可能性。根据本RFA的要求，我们将招募一组重度和中度哮喘成人和儿童，并对他们进行为期三年的跟踪调查。糖皮质激素对ALX轴的影响以及与炎症和重塑标记物的相互作用将通过在登记时静脉注射糖皮质激素前和1个月后采集血液和呼吸道样本来检验。这些受试者的临床病程(特别是病情恶化和肺活量测定)将被监测3年以上，随后将重复使用非肠道皮质类固醇。将评估血液和痰中ALX轴激素后表型的稳定性，并通过比较研究开始和3年后(皮质类固醇后)进行的高分辨率CT扫描来评估其与呼吸道重塑的关系。为了验证我们的假设，我们提出了两个主要的具体目标：1.确定糖皮质激素对重症和非重症哮喘患者ALX轴的影响，以及2.明确ALX异常表型与呼吸道炎症和进展性疾病的关系。这项研究的长期目标是全面了解ALX轴的扰动对严重哮喘发病机制的影响，以及该轴的组成部分(特别是脂氧素)作为可能的新型治疗药物缓解严重哮喘过度发病率的可能性。

DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that ALX axis dysregulation underlies persistent asthma and airway inflammation despite corticosteroid therapy in a cohort of patients with severe asthma. Lipoxin A4 (LXA4) is an anti-inflammatory and pro-resolving mediator that can interact with specific receptors (i.e., ALX/FPR2) to inhibit allergic airway inflammation and hyper-responsiveness in model systems. Severe asthma is characterized by decreased LXA4, suggesting that this condition may stem from a defect in counter-regulation. There are three additional ligands for ALX/FPR2 receptors, namely 15- epimer-LXA4, annexin A1 and serum amyloid A. All four ALX/FPR2 ligands are generated in asthma and together with ALX/FPR2 receptors comprise the "ALX axis." Of note, both protein ligands can be induced in vitro by corticosteroids, the most common asthma controller therapy, and unlike the other three ligands, serum amyloid a interactions with ALX/FPR2 paradoxically promotes inflammation, raising the possibility that a subset of patients with severe asthma may experience detriment rather than benefit from corticosteroids. Consistent with the requests of this RFA, we will recruit and characterize a cohort of severe and moderate adults and children with asthma and follow them for three years. The effects of corticosteroids on the ALX axis and the interaction with inflammatory and remodeling markers will be examined by obtaining blood and respiratory specimens before and 1 month after parenteral corticosteroids at enrollment. The clinical course of these subjects (particularly exacerbations and spirometry) will be monitored over 3 years followed by a repeat course of parenteral corticosteroids. The stability of the ALX axis phenotype post-corticosteroids will be assessed In blood and sputum, and its relationship to airway remodeling will be assessed by comparing high resolution CT scans performed (after corticosteroids) at the beginning and after 3 years in the study. To test our hypothesis, we propose two principal specific aims: 1. Determine the effect of corticosteroids on the ALX axis in severe and non-severe asthma, and 2. Define the relationship between the ALX aberrant phenotype and airway inflammation and progressive disease. The long-term goals for this research is to develop a comprehensive understanding of the perturbations in the ALX axis to the pathogenesis of severe asthma and the potential for components of this axis (lipoxins in particular) as possible novel therapeutic agents to alleviate severe asthma's excess morbidity.