Regulation of Pulmonary Inflammation by Leukotriene E4

性状（由申请方提供）：白三烯（LT）E4是半胱氨酰白三烯（cys-LT）生成的终末产物，是经典半胱氨酰白三烯受体（CysLTR）的弱激动剂，但在人体中是支气管嗜酸性粒细胞增多和气道高反应性的强效诱导剂。LTE 4大量存在于哮喘患者的气道中，尤其是在阿司匹林加重呼吸道疾病（AERD）患者的肺和鼻组织中。ADP是一种丰富的胞外核苷酸，是P2 Y12和P2 Y1受体的天然配体。在目前的资助期间，我们确定LTE 4通过完全独立于经典CysLTR的途径显着增强致敏小鼠的气道炎症，并且需要P2 Y12受体和血小板。然而，令人惊讶的是，LTE 4在P2 Y12受体上没有表现出直接结合。我们已经发现ADP是体内LTE 4的分子模拟物，具有作为肺部炎症放大器的潜在功能。该提案的继续重点是负责LTE 4在肺部炎症中的作用的机制和细胞靶点，以及P2 Y12受体在此过程中的作用。这些发现预计将对哮喘的病理生理学和治疗产生直接影响，特别是在AERD中，其中有一个由cys-LT驱动的疾病的实质性组成部分。这一建议是基于中心假设，1。P2 Y12受体介导会聚途径，通过该途径，二磷酸腺苷（ADP）和白三烯（LT）E4分别促进效应细胞通过血小板依赖性机制迁移到变应原攻击的肺，和2。P2 Y12受体与至少一个额外的GPCR相互作用以产生LTE 4的功能性受体，并且还与P2 Y1受体相互作用以形成ADP的受体复合物。这些复合物分别介导P2 Y12受体对肺部炎症的LTE 4依赖性和LTE 4独立性特征。 公共卫生相关性：白三烯E4（LTE 4）是一种由人体免疫系统产生的化学物质，可引起炎症。高水平的LTE 4存在于哮喘患者的肺部，这是一种常见的严重疾病。该提案旨在确定使LTE 4能够引起炎症的细胞和分子。目标是找到更有效的治疗哮喘和其他过敏性疾病的方法。

DESCRIPTION (provided by applicant): Leukotriene (LT)E4, the terminal product of cysteinyl leukotriene (cys-LT) generation, is a weak agonist of the classical cysteinyl leukotriene receptors (CysLTRs), but a potent inducer of bronchial eosinophilia and airway hyperresponsiveness in humans. LTE4 abounds in the airways of asthmatics, and is especially abundant in the lungs and nasal tissues of patients with aspirin-exacerbated respiratory disease (AERD). ADP, an abundant extracellular nucleotide, is the natural ligand for P2Y12 and P2Y1 receptors. In the current funding period, we determined that LTE4 markedly potentiates airway inflammation in sensitized mice through a pathway that is completely independent of classical CysLTRs, and requires both P2Y12 receptors and platelets. Surprisingly, however, LTE4 exhibits no direct binding at P2Y12 receptors. We have found that ADP is a molecular mimic of LTE4 in vivo, with potential function as an amplifier of pulmonary inflammation. The continuation of this proposal focuses on the mechanism(s) and cellular targets that are responsible for the effects of LTE4 in pulmonary inflammation, and the role of P2Y12 receptors in this process. The findings are expected to have immediate implications for asthma pathophysiology and treatment, especially in AERD, in which there is a substantial component of the disease that is driven by cys-LTs. This proposal is based on the central hypotheses that 1. P2Y12 receptors mediate a convergent pathway by which adenosine diphosphate (ADP) and leukotriene (LT)E4, respectively, facilitate the migration of effector cells to the allergen-challenged lung through platelet-dependent mechanisms, and 2. P2Y12 receptors interact with at least one additional GPCR to create a functional receptor for LTE4, and also interact with P2Y1 receptors to form a receptor complex for ADP. These complexes mediate the respective LTE4-dependent and LTE4-indepedent features of P2Y12 receptor contributions to pulmonary inflammation. PUBLIC HEALTH RELEVANCE: Leukotriene E4 (LTE4) is a chemical produced by the body's immune system that causes inflammation. High levels of LTE4 are present in the lungs of patients with asthma, a common serious disease. This proposal seeks to identify the cells and molecules that enable LTE4 to cause inflammation. The goal is to find more effective treatments for asthma and other allergic diseases.