| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
*Department of Microbiology and Immunology,
Department of Biochemistry and Molecular Biology, and
Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555;
Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, México; and
¶Institute of Immunology, Medical and Health Science Center, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
The prevalence of allergies and asthma among the world’s population has been steadily increasing due to environmental factors. It has been described that exposure to ozone, diesel exhaust particles, or tobacco smoke exacerbates allergic inflammation in the lungs. These environmental oxidants increase the levels of cellular reactive oxygen species (ROS) and induce mitochondrial dysfunction in the airway epithelium. In this study, we investigated the involvement of preexisting mitochondrial dysfunction in the exacerbation of allergic airway inflammation. After cellular oxidative insult induced by ragweed pollen extract (RWE) exposure, we have identified nine oxidatively damaged mitochondrial respiratory chain-complex and associated proteins. Out of these, the ubiquinol-cytochrome c reductase core II protein (UQCRC2) was found to be implicated in mitochondrial ROS generation from respiratory complex III. Mitochondrial dysfunction induced by deficiency of UQCRC2 in airway epithelium of sensitized BALB/c mice prior the RWE challenge increased the Ag-induced accumulation of eosinophils, mucin levels in the airways, and bronchial hyperresponsiveness. Deficiency of UQCRC1, another oxidative damage-sensitive complex III protein, did not significantly alter cellular ROS levels or the intensity of RWE-induced airway inflammation. These observations suggest that preexisting mitochondrial dysfunction induced by oxidant environmental pollutants is responsible for the severe symptoms in allergic airway inflammation. These data also imply that mitochondrial defects could be risk factors and may be responsible for severe allergic disorders in atopic individuals.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Allergy and Infectious Diseases Grant P01 AI062885-01 (to I.B. and S.S.), National Institutes of Health Grant HL071163 (to S.S. and I.B.), National Institutes of Health, National Heart, Lung, and Blood Institute Proteomics Initiative NO1HV-28184 (to A.K.), National Institute on Environmental Health Sciences Center Grant EOS 006677 (to I.B. and A.K.), and the Hungarian Scientific Research Fund 73347 (to A.B.).
2 Address correspondence and reprint requests to Dr. Istvan Boldogh, Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555. E-mail: sboldogh{at}utmb.edu
3 Abbreviations used in this paper: ROS, reactive oxygen species; ASO, antisense oligonucleotides; BALF, bronchoalveolar lavage fluid; Cox IIb, cytochrome c oxidase subunit IIb; DAPI, 4,6'-diamidino-2-phenylindole; DCF, dichlorofluorescein; DNPH, 4-dinitrophenylhydrazine; DPI, diphenylene iodonium; H2DCF-DA, 2'-7'-dihydro-dichlorofluorescein diacetate; mtDNA, mitochondrial DNA; MRC, mitochondrial respiratory complex; NAC, N-acetyl-L-cysteine; NDUFS1, NADH dehydrogenase (ubiquinone) Fe-S protein 1; NDUFS2, NADH dehydrogenase (ubiquinone) Fe-S protein 2; 3-NPA, 3-nitropropionic acid; Penh, enhanced pause; RWE, ragweed pollen extract; UQCRC1, ubiquinol-cytochrome c reductase core protein I; UQCRC2, ubiquinol-cytochrome c reductase core protein II.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
