Regulation of Pulmonary Inflammation by Leukotriene E4

描述(由申请人提供)：白三烯(LT)E4是半胱氨酰白三烯(Cys-LT)产生的最终产物，是经典的半胱氨酰白三烯受体(CysLTRs)的弱激动剂，但却是人类支气管嗜酸性粒细胞增多和呼吸道高反应性的有力诱导剂。LTE4在哮喘患者的呼吸道中含量丰富，在阿司匹林加重的呼吸系统疾病(AERD)患者的肺和鼻部组织中尤其丰富。ADP是一种丰富的胞外核苷酸，是P2Y12和P2Y1受体的天然配体。在目前的资助期间，我们确定LTE4通过一条完全独立于经典CysLTRs的途径显著增强致敏小鼠的呼吸道炎症，并需要P2Y12受体和血小板。然而，令人惊讶的是，LTE4没有与P2Y12受体直接结合。我们发现ADP是体内LTE4的分子模拟物，具有潜在的肺部炎症放大作用。这一建议的继续关注于LTE4在肺部炎症中的作用机制(S)和细胞靶点，以及P2Y12受体在这一过程中的作用。这些发现有望对哮喘的病理生理学和治疗产生直接影响，特别是在AERD，在AERD中，有很大一部分疾病是由Cys-LTS驱动的。这一建议基于以下中心假设：1.P2Y12受体分别通过介导二磷酸腺苷(ADP)和白三烯(LT)E4的汇聚途径，通过血小板依赖机制促进效应细胞向过敏原攻击的肺组织迁移；2.P2Y12受体与至少一个额外的GPCR相互作用，产生LTE4的功能性受体，并与P2Y1受体相互作用，形成ADP的受体复合体。这些复合体分别介导了P2Y12受体对肺部炎症的LTE4依赖性和非LTE4依赖性的作用。

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.