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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI062885-02
Application #
7310258
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$201,877
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Tian, Bing; Widen, Steven G; Yang, Jun et al. (2018) The NF?B subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells. J Biol Chem 293:16528-16545
Graber, Ted G; Rawls, Brandy L; Tian, Bing et al. (2018) Repetitive TLR3 activation in the lung induces skeletal muscle adaptations and cachexia. Exp Gerontol 106:88-100
Tian, Bing; Yang, Jun; Zhao, Yingxin et al. (2018) Central Role of the NF-?B Pathway in the Scgb1a1-Expressing Epithelium in Mediating Respiratory Syncytial Virus-Induced Airway Inflammation. J Virol 92:
Tian, Bing; Hosoki, Koa; Liu, Zhiqing et al. (2018) Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. J Allergy Clin Immunol :
Wang, Ruoxi; Hao, Wenjing; Pan, Lang et al. (2018) The roles of base excision repair enzyme OGG1 in gene expression. Cell Mol Life Sci 75:3741-3750
Tian, Bing; Liu, Zhiqing; Yang, Jun et al. (2018) Selective Antagonists of the Bronchiolar Epithelial NF-?B-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. Cell Rep 23:1138-1151
Ba, Xueqing; Boldogh, Istvan (2018) 8-Oxoguanine DNA glycosylase 1: Beyond repair of the oxidatively modified base lesions. Redox Biol 14:669-678
Visnes, Torkild; Cázares-Körner, Armando; Hao, Wenjing et al. (2018) Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 362:834-839
Ochoa, Lorenzo F; Kholodnykh, Alexander; Villarreal, Paula et al. (2018) Imaging of Murine Whole Lung Fibrosis by Large Scale 3D Microscopy aided by Tissue Optical Clearing. Sci Rep 8:13348
Liu, Zhiqing; Tian, Bing; Chen, Haiying et al. (2018) Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. Eur J Med Chem 151:450-461

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