Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid

^a Departments of Medicine and Pathology, The Montreal General Hospital, McGill University, Montreal, Quebec, Canada H3G 1A4; GenPath Laboratories, Montreal, Quebec, Canada
^b National Heart and Lung Institute, London, England

Peroxynitrite is a potent oxidant formed by the rapid reaction of the free radicals nitric oxide (NO) and superoxide. It causes airway hyperresponsiveness and airway epithelial damage, enhances inflammatory cell recruitment, and inhibits pulmonary surfactant. Asthma is characterized by increased airway hyperresponsiveness, airway epithelial shedding, and inflammation. We examined the production of peroxynitrite and the expression of inducible nitric oxide synthase (iNOS) in airways of asthmatic patients compared to normal control subjects. We also performed a double-blind, crossover randomized-order, placebo-controlled study on 10 asthmatic patients to study the effects of inhaled glucocorticoid treatment (Budesonide) on the formation of peroxynitrite and NO. Fiberoptic bronchial biopsies were examined by immunohistochemistry with antiserum to nitrotyrosine, a marker of protein nitration by peroxynitrite. We also examined the expression of iNOS by immunohistochemistry and in situ hybridization, and measured exhaled NO by chemiluminescence. We correlated the airway production of peroxynitrite with pulmonary functions and airway responsiveness. In airway passages of control subjects, there was weak or no nitrotyrosine immunoreactivity. In contrast, there was strong immunoreactivity for nitrotyrosine in the airway epithelium and inflammatory cells in the airways of persons with asthma. Budesonide treatment resulted in a significant reduction in nitrotyrosine immunoreactivity. Expression of iNOS was evident in the airway pithelium of controls and asthmatic patients, but was significantly more abundant in asthmatic patients. The presence of nitrotyrosine in the airway epithelium (r=-0.841, P<0.0001; r=-0.771, P=0.0004) and inflammatory cells (r=-0.727, P=0014; r=-0.681, P=0.004) correlated inversely with methacholine PC₂₀ and forced expiratory volume in 1 s, respectively. Asthma is associated with increased peroxynitrite formation in the airways, which is reduced after Budesonide treatment. The potent oxidant peroxynitrite may contribute to airway obstruction and hyperresponsiveness and epithelial damage in asthma.—Saleh, D., Ernst, P., Lim, S., Barnes, P. J., Giaid, A. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J. 12, 929–937 (1998)

Key Words: nitrotyrosine • asthma • steroids • human

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				F. H. Guo, S. A. A. Comhair, S. Zheng, R. A. Dweik, N. T. Eissa, M. J. Thomassen, W. Calhoun, and S. C. Erzurum Molecular Mechanisms of Increased Nitric Oxide (NO) in Asthma: Evidence for Transcriptional and Post-Translational Regulation of NO Synthesis J. Immunol., June 1, 2000; 164(11): 5970 - 5980. [Abstract] [Full Text] [PDF]

				H. E. Marshall and J. S. Stamler NO Waiting to Exhale in Asthma Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): 685 - 687. [Full Text] [PDF]

				S. Lim, A. Jatakanon, S. Meah, T. Oates, K. F. Chung, and P. J Barnes Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in mild to moderately severe asthma Thorax, March 1, 2000; 55(3): 184 - 188. [Abstract] [Full Text]

				R. TAHA, R. OLIVENSTEIN, T. UTSUMI, P. ERNST, P. J. BARNES, I. W. RODGER, and A. GIAID Prostaglandin H Synthase 2 Expression in Airway Cells from Patients with Asthma and Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): 636 - 640. [Abstract] [Full Text]

				E. Sato, K. L. Simpson, M. B. Grisham, S. Koyama, and R. A. Robbins Effects of Reactive Oxygen and Nitrogen Metabolites on Eotaxin-Induced Eosinophil Chemotactic Activity In Vitro Am. J. Respir. Cell Mol. Biol., January 1, 2000; 22(1): 61 - 67. [Abstract] [Full Text]

				F. L. M. Ricciardolo, L. Vergnani, S. Wiegand, F. Ricci, N. Manzoli, A. Fischer, S. Amadesi, R. Fellin, and P. Geppetti Detection of Nitric Oxide Release Induced by Bradykinin in Guinea Pig Trachea and Main Bronchi Using a Porphyrinic Microsensor Am. J. Respir. Cell Mol. Biol., January 1, 2000; 22(1): 97 - 104. [Abstract] [Full Text]

				R. DWORSKI, J. J. MURRAY, L. JACKSONROBERTS II, J. A. OATES, J. D. MORROW, L. FISHER, and J. R. SHELLER Allergen-induced Synthesis of F2-Isoprostanes in Atopic Asthmatics . Evidence for Oxidant Stress Am. J. Respir. Crit. Care Med., December 1, 1999; 160(6): 1947 - 1951. [Abstract] [Full Text]

				E. GABBAY, E. HAYDN WALTERS, B. ORSIDA, H. WHITFORD, C. WARD, T. C. KOTSIMBOS, G. I. SNELL, and T. J. WILLIAMS In Stable Lung Transplant Recipients, Exhaled Nitric Oxide Levels Positively Correlate with Airway Neutrophilia and Bronchial Epithelial iNOS Am. J. Respir. Crit. Care Med., December 1, 1999; 160(6): 2093 - 2099. [Abstract] [Full Text]

				Y. STERN, A. SALZMAN, R. T. COTTON, and B. ZINGARELLI Protective Effect of 3-Aminobenzamide, an Inhibitor of Poly (ADP-Ribose) Synthetase, against Laryngeal Injury in Rats Am. J. Respir. Crit. Care Med., November 1, 1999; 160(5): 1743 - 1749. [Abstract] [Full Text]

				W. Wu, Y. Chen, and S. L. Hazen Eosinophil Peroxidase Nitrates Protein Tyrosyl Residues. IMPLICATIONS FOR OXIDATIVE DAMAGE BY NITRATING INTERMEDIATES IN EOSINOPHILIC INFLAMMATORY DISORDERS J. Biol. Chem., September 3, 1999; 274(36): 25933 - 25944. [Abstract] [Full Text] [PDF]

				E. Sato, K. L. Simpson, M. B. Grisham, S. Koyama, and R. A. Robbins Effects of reactive oxygen and nitrogen metabolites on MCP-1-induced monocyte chemotactic activity in vitro Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L543 - L549. [Abstract] [Full Text] [PDF]

				E. Sato, K. L. Simpson, M. B. Grisham, S. Koyama, and R. A. Robbins Effects of Reactive Oxygen and Nitrogen Metabolites on RANTES- and IL-5-Induced Eosinophil Chemotactic Activity in Vitro Am. J. Pathol., August 1, 1999; 155(2): 591 - 598. [Abstract] [Full Text] [PDF]

				A. van der VLIET, J. P. EISERICH, M. K. SHIGENAGA, and C. E. CROSS Reactive Nitrogen Species and Tyrosine Nitration in the Respiratory Tract . Epiphenomena or a Pathobiologic Mechanism of Disease? Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 1 - 9. [Full Text]

				P. MONTUSCHI, M. CORRADI, G. CIABATTONI, J. NIGHTINGALE, S. A. KHARITONOV, and P. J. BARNES Increased 8-Isoprostane, a Marker of Oxidative Stress, in Exhaled Condensate of Asthma Patients Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 216 - 220. [Abstract] [Full Text]

				P J STERK, H W F M DE GOUW, F L M RICCIARDOLO, and K F RABE Exhaled nitric oxide in COPD: glancing through a smoke screen Thorax, July 1, 1999; 54(7): 565 - 567. [Full Text]

				G. T. De Sanctis, J. A. MacLean, K. Hamada, S. Mehta, J. A. Scott, A. Jiao, C. N. Yandava, L. Kobzik, W. W. Wolyniec, A. J. Fabian, et al. Contribution of Nitric Oxide Synthases 1, 2, and 3 to Airway Hyperresponsiveness and Inflammation in a Murine Model of Asthma J. Exp. Med., May 17, 1999; 189(10): 1621 - 1630. [Abstract] [Full Text] [PDF]

				P. J. Barnes, K. F. Chung, and C. P. Page Inflammatory Mediators of Asthma: An Update Pharmacol. Rev., December 1, 1998; 50(4): 515 - 596. [Abstract] [Full Text] [PDF]

				A. S. Haqqani, J. F. Kelly, and H. C. Birnboim Selective Nitration of Histone Tyrosine Residues in Vivo in Mutatect Tumors J. Biol. Chem., January 25, 2002; 277(5): 3614 - 3621. [Abstract] [Full Text] [PDF]

				M. Kirsch and H. de Groot Ascorbate Is a Potent Antioxidant against Peroxynitrite-induced Oxidation Reactions. EVIDENCE THAT ASCORBATE ACTS BY RE-REDUCING SUBSTRATE RADICALS PRODUCED BY PEROXYNITRITE J. Biol. Chem., May 26, 2000; 275(22): 16702 - 16708. [Abstract] [Full Text] [PDF]

				R. A. Dweik, S. A. A. Comhair, B. Gaston, F. B. J. M. Thunnissen, C. Farver, M. J. Thomassen, M. Kavuru, J. Hammel, H. M. Abu-Soud, and S. C. Erzurum NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response PNAS, February 27, 2001; 98(5): 2622 - 2627. [Abstract] [Full Text] [PDF]