Regulation of Pulmonary Prostaglandins by Leukotriene E4

白三烯(LT)E4是半胱氨酰白三烯(Cys-LTS)最稳定的配体，通过其激活肥大细胞(MC)和促进肺部炎症的机制和受体。大量的历史信息支持LTE4受体的存在我们发表的研究表明，LTE4是体外对人MC增殖和在体内增强呼吸道炎症作用最强的Cys-LT，它通过一种独立于CysLT1R和CysLT2R的机制激活人MC。我们的初步研究有力地表明，P2Y12受体是一种二磷酸腺苷反应性GPCR，也是LTE4反应性受体(以下简称P2Y12/CysLT3R)，在体外介导LTE4对MC的作用，在体内对肺组织病理也有影响。中心假设是LTE4，已知受体上Cys-LT中最弱的激动剂，是与促进过敏性粘膜炎症最相关的Cys-LT。一个推论是，LTE4的作用是由一个以前未被发现的Cys-LT反应性G蛋白偶联受体(GPCR)介导的，以下称为“P2Y12/CysLT3R”。目的1用体外实验方法证明P2Y12/CysLT3R是一种真正的LTE4反应性受体。目的2试图证明P2Y12/CysLT3R在体内解释了LTE4在肺内显著的促炎作用，并确定了这种作用的基本细胞靶点。这一发现有望对哮喘的病理生理学和治疗产生直接影响。 ?？ ?？ ?？ ?？

This proposal seeks to determine the mechanisms and receptors by which leukotriene (LT)E4, the most stable ligand of the cysteinyl leukotrienes (cys-LTs), activates mast cells (MCs) and promotes pulmonary inflammation. An abundance of historical information supports the existence of a distinct receptor for LTE4 Our published studies demonstrate that LTE4 is the most potent cys-LT for both for human MC proliferation in vitro and potentiation of airway inflammation in vivo, and it activates human MCs by a mechanism independent of CysLT1R and CysLT2R. Our Preliminary Studies strongly indicate that the P2Y12 receptor, an adenosine diphosphate-responsive GPCR, is also the LTE4-reactive receptor (hereafter termed P2Y12/CysLT3R) mediating the effects of LTE4 on MCs in vitro and on lung pathology in vivo. The central hypothesis is that LTE4, the weakest agonist of the cys-LTs at their known receptors, is the most relevant cys-LT for promoting allergic mucosal inflammation. A corollary hypothesis is that the actions of LTE4 are mediated by a previously unrecognized cys-LT-reactive G protein-coupled receptor (GPCR), hereafter referred to as "P2Y12/CysLT3R". Aim 1 uses in vitro approaches to prove that P2Y12/CysLT3R is a true LTE4-reactive receptor. Aim 2 seeks to prove that P2Y12/CysLT3R accounts for the striking proinflammatory effects of LTE4 in the lung in vivo, and to identify the essential cellular targets of this effect. The findings are expected to have immediate implications for asthma pathophysiology and treatment. ?? ?? ?? ??