Project 5 (Boldogh, I.)
Istvan Boldogh, PhD
Associate Professor in Microbiology and Immunology
3.142 Medical Research Building
Department of Microbiology and Immunology
301 University Blvd.
Galveston, TX 77555-1070
Dr. Boldogh's bio...
Allergic asthma is a disorder of the airways in which antigens trigger T helper-type 2 (Th2) pulmonary inflammation, resulting in infiltration of eosinophils into the lungs, airway hyperreactivity, mucus hypersecretion and the production of IgE. Despite the clear role of Th2 responses in asthma pathogenesis, the exact etiopathogenesis is still elusive. Little is known about the “adjuvant-induced” cellular events that synergize with inhaled antigens to induce allergic inflammation.
We have shown that exposure to pollen grains (trees, weeds), subpollen particles (PP) or molds (e.g., Alternaria, Aspergillus, and Penicillium) dramatically increase intracellular levels of reactive oxygen species (ROS) in the airway epithelium and cultured epithelial cells. Mitochondrial injury in airway epithelium occurs via oxidative insults generated by PP or molds intrinsic NADPH oxidase(s) activity. NADPH oxidase-mediated oxidative stress results in a transient decrease in inner membrane potential, changes in permeability transition pore opening, as well as sustained generation of superoxide anion (O2.-). O2.- is converted into readily diffusible H2O2 by superoxide dismutases. Mitochondrial ROS release may be decreased (or increased) by specific respiratory complex inhibitors. We have recently tested the effect of some complex(es) inhibitors on PP-induced allergic inflammation in an experimental mouse model. Co-administration of rotenone (inhibits electron flow from complex I to complex III) with ragweed PP significantly decreased lung inflammation. In contrast, antimycin A (inhibits complex III at matrix-side of mitochondria inner membrane) strongly augmented ROS generation, accumulation of eosinophils, mucus production and airway hyperreactivity. Addition of these inhibitors 12 hours after ragweed PP challenge did not significantly affect the outcome of RWPP-triggered airway inflammation. Similar observations were made in a mouse model of conjunctivitis. Based on these data we propose a novel hypothesis of “mitochondria-driven” allergen-induced inflammation.
The central hypothesis of Dr. Boldogh's project is that environmental pollutants and redox-active plant/mold aero-allergenic particles cause mitochondrial dysfunction and sustained release of ROS from respiratory complexes leading to inflammatory chemokine production via NF-kB-dependent gene network and vigorous antigen-driven allergic inflammation. This hypothesis is being tested by the following specific aims:
- To establish whether overexpression of inflammatory mediators, increased mucus production in airway epithelium and airway hyper-reactivity is dependent on mitochondrial function.
- To identify the mechanism and mitochondrial site for ROS generation and damage to electron transport complexes in airway epithelial cells after challenge with redox-active aeroallergens.
- To determine mitochondrial-driven activation of NF-kB-dependent gene network in airway epithelial cells. The goals of this project to show that mitochondrial disfunction results in sustained ROS release, which then generate critical signals required for chemokine production through NF-kB-dependent gene expression, causing vigorous antigen-driven allergic inflammation in asthma.
Understanding how mitochondria in the epithelium respond to oxidative insults induced by allergenic complexes will identify new targets whose activities may be modulated to control inflammation in the lungs.
- Choudhury BK, Wild JS, Alam R, Klinman DM, Boldogh I, Dharajiya N, Mileski WJ, Sur S. In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J. Immunol. 169:5955-5961, 2002
- Brasier, AR., Spratt, H., Wu, Z., Boldogh, I., Zhang, Y., Garofalo, RP., Casola, A., Pashmi, J., Haag, A., Luxon, B., and Kurosky, A. Nuclear heat shock response and novel nuclear domain 10 reorganization in respiratory syncytial virus-infected A549 cells identified by high resolution 2D gel electrophoresis. J. Virology. 78; 11461-11476, 2004
- Bacsi, A., Choudhury, B.K., Dharajiya, N., Sur, S., and Boldogh, I. Impact of pollen-mediated oxidative stress on hypersensitivity reactions and lat-phase inflammation in allergic conjunctivitis. J. Allergy Clinical Immunology In Press, 2005.
- Boldogh, I., A. Bacsi, B.K. Choudhury, N. Dharajiya, R. Alam, T. Hazra, S. Mitra, R. Goldblum, and S. Sur
ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation
J. Clin. Invest., Aug 2005; 115: 2169 - 2179.
- Endo, S., Midoru-Horiuti, T., Boldogh, I., Sur, S., Goldblum, RM., and Brooks, EG. IgE-independent mast cell degranulation and IL-4 production by cedar pollen: a novel mechanism dependent on generation of reactive oxygen intermediates. Submitted for publication, 2005
- Bacsi, A., M. Woodberry, J. Papaconstantinou and I. Boldogh, Localization of Superoxide Anion Production to Mitochondrial Electron Transport Chain in 3-NPA-Treated Cells. Submitted for publication, 2005
- Bacsi, A., Choudhury, B.K., Dharajiya, N., Brooks, ED., Sur, S., and Boldogh, I. Mitochondrial dysfunction: IgE independent cell degranulation and chemokine production. In preparation, 2005
International Meeting Presentations:
- Bacsi, A., Sur, S., Choudhury, B.K., Alam, R. and Boldogh, I.: Pro-oxidant activity of pollen and mold proteins induces oxidative stress in the lungs independent of adaptive immunity. American Academy of Allergy, Asthma and Immunology, J. Allergy Clin. Immunol. 111, S340, 2003.
- Bacsi, A., Sur, S., Choudhury, B.K., Hazra, T.K. and Boldogh, I.: Plant pollens and molds directly induce oxidative stress in the airways. Free Rad. Biol. Med. 33, S343, 2002.
- Choudhury, B.K., J.S. Wild, N. Dharajiya, A. Bacsi, R. Alam, I. Boldogh, and S. Sur. Stimulation of Innate Immune Response Induces Long Term Allergic Sensitization and Allergic Airway Inflammation Independent of STAT-6. AAAI, J. Allergy Clin. Immunol. 113, S163, 2004.
- Bacsi, A., N. Dharajiya, B.K. Choudhury, S. Sur, I. Boldogh. Reactive Oxygen Species Generated by Pollen Grain’s NAD(P) Oxidase Augment Allergic Ocular Symptoms. AAAI, J. Allergy Clin. Immunol. 113, S164, 2004.
- Boldogh, I., A. Bacsi, B.K. Choudhury, N. Dharajiy, R. Alam, S. Sur. Oxidative Stress Generated by Intrinsic Pollen NADPH Oxidases Is Required for Inducing Allergic Airway Inflammation. AAAI, J. Allergy Clin. Immunol.113, S164, 2004.
- Bloebaum, R.M., I. Boldogh, L.A. Bruce, S. Sur. Intrinsic Pollen NADPH Oxidases Induce Genes by Activating Innate Immune Responses in Human Bronchial Epithelial Cells. AAAI, J. Allergy Clin. Immunol. 113, S330, 2004.