Oxidative Stress: Antigen-Induced Allergic Inflammation

我们提供的证据表明，亚花粉颗粒含有主要的抗原过敏成分， 豚草花粉粒具有强的NAD（P）H氧化酶活性。支气管气道暴露 上皮细胞转化为亚花粉颗粒改变线粒体通透性转换孔径、内膜电位并介导持续的ROS产生。用这些颗粒激发致敏小鼠诱导强烈的过敏性炎症、高反应性和粘蛋白产生。鱼藤酮是线粒体电子传递链中从复合物I到复合物III的电子流的抑制剂，其显著降低，而用亚花粉颗粒+抗霉素A（增加复合物III的膜间侧的H2 O2产生）共同攻击小鼠增强哮喘实验小鼠模型中的气道炎症和粘蛋白产生。我们提出了一种新的“线粒体信号”假说，其中抗原呈递给辅助性T细胞2通过特异性T细胞识别产生“抗原介导的信号”，受损的线粒体传递促进信号，导致剧烈的过敏性气道炎症。 该项目的中心假设是，亚花粉颗粒引发的氧化损伤， 线粒体导致细胞氧化应激水平的持续增加， 炎性趋化因子产生和剧烈的抗原驱动的过敏性炎症。 我们将通过检查亚花粉颗粒是否诱导1）依赖于ROS的线粒体释放的气道上皮中炎症介质和粘液的过度表达; 2）线粒体膜和呼吸复合体的损伤，其成为气道上皮细胞中ROS产生的位点;和3）线粒体ROS介导的NF-κ B依赖性基因网络的活化，用于在气道上皮细胞中产生促炎介质。我们的目标是阐明通过使用增加线粒体能力以预防或科普氧化损伤或抑制线粒体呼吸复合体处ROS产生的治疗剂来治疗致敏个体中的过敏性炎症的基础。

We provide evidence that subpollen particles contains major antigenic allergenic components of ragweed pollen grains and have robust NAD(P)H oxidase activity. Exposure of bronchial airway epithelial cells to subpollen particles changes mitochondrial permeability transition pore size, inner membrane potential and mediate sustained ROS production. Challenge of sensitized mice with these particles induce robust allergic inflammation, hyper responsiveness and mucin production. Rotenone, an inhibitor of electron flow from complex I to complex III in the mitochondria electron transport chain significantly decreased, while, co-challenge of mice with subpollen particles+ antimycin A (increase H2O2 production from inter-membrane side of complex III) augments airway inflammation and mucin production in experimental mouse model of asthma. We propose a novel "mitochondrial signal" hypothesis in which antigen presentation to T-helper 2 cells generates an "antigen-mediated signal" via specific T-cell recognition and injured mitochondria deliver a facilitating signal resulting in vigorous allergic airway inflammation. The central hypothesis of this project is that subpollen particle-initiated oxidative injury to mitochondria result in sustained increase in cellular oxidative stress level that is required for inflammatory chemokine production and vigorous antigen-driven allergic inflammation. We will test our hypothesis by examining whether sub-pollen particles induce 1) overexpression of inflammatory mediators and mucus in airway epithelium that is dependent on mitochondrial release of ROS ; 2) damage to mitochondrial membranes and respiratory complexes, which become the site for ROS generation in airway epithelial cells; and 3) mitochondrial ROS-mediated activation of NF-kappaB-dependent gene network for production of pro-inflammatory mediators in airway epithelial cells. Our goals are to elucidate the basis for therapeutic invention of allergic inflammation in sensitized individuals by use of therapeutics that increases mitochondria capacity to prevent or cope with oxidative injury or suppress ROS generation at the mitochondrial respiratory complexes.