Oxidative Stress: Antigen-Induced Allergic Inflammation

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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.