LS Feder, D Stelts, RW Chapman, D Manfra, Y Crawley, H Jones, M Minnicozzi, X Fernandez, T Paster, RW Egan, W Kreutner and TT Kung
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.

Nitric oxide (NO) is an important mediator of inflammatory reactions and may contribute to the lung inflammation in allergic pulmonary diseases. To assess the role of NO in pulmonary inflammation, we studied the effect of four nitric oxide synthase (NOS) inhibitors, N- nitro-L-arginine methyl ester (L-NAME), aminoguanidine, N(G)-monomethyl- L-arginine (NMMA) and L-N6-(1-Iminoethyl) lysine (L-NIL), on the influx of eosinophils into the bronchoalveolar lavage (BAL) fluid and lung tissue of antigen-challenged allergic mice. We also analyzed lung tissues for the presence of steady state mRNA for inducible nitric oxide synthase (iNOS) and iNOS protein. Furthermore, BAL fluid and serum were analyzed for their nitrite content. B6D2F1/J mice were sensitized to ovalbumin (OVA) and challenged with aerosolized OVA. The NOS inhibitors were given 0.5 h before and 4 h after the antigen challenge. OVA challenge induced a marked eosinophilia in the BAL fluid and lung tissue 24 h after challenge. The OVA-induced pulmonary eosinophilia was significantly reduced by L-NAME (10 and 50 mg/kg, intraperitoneally [i.p.]). The inactive isomer, D-NAME (50 mg/kg, i.p.) had no effect. When mice were treated with L-NAME (20 mg/kg, i.p.) and an excess of NOS substrate, L-arginine (200 mg/kg, i.p.), the OVA- induced pulmonary eosinophilia was restored. Treatment with aminoguanidine (0.4-50 mg/kg, i.p.) also reduced the pulmonary eosinophilia. Treatment with NMMA (2-50 mg/kg, i.p.) partially reduced the eosinophilia, but L-NIL (10-50 mg/kg, i.p.), a selective iNOS inhibitor, had no effect. L-NAME had no effect on the reduction of eosinophils in the bone marrow following OVA challenge to sensitized mice. OVA challenge to sensitized mice had no effect on iNOS protein expression or iNOS mRNA in the lungs or on the levels of nitrite in the BAL fluid. These results suggest that NO is involved in the development of pulmonary eosinophilia in allergic mice. The NO contributing to the eosinophilia is not generated through the activity of iNOS nor does NO contribute to the efflux of eosinophils from the bone marrow in response to antigen challenge. It is speculated that after antigen challenge, the localized production of NO, possibly from pulmonary vascular endothelial cells, is involved in the extravasation of eosinophils from the circulation into the lung tissue.

This article has been cited by other articles:

				C. C. Dong, X. J. Yin, J. Y. C. Ma, L. Millecchia, M. W. Barger, J. R. Roberts, X.-D. Zhang, J. M. Antonini, and J. K. H. Ma Exposure of Brown Norway Rats to Diesel Exhaust Particles Prior to Ovalbumin (OVA) Sensitization Elicits IgE Adjuvant Activity but Attenuates OVA-Induced Airway Inflammation Toxicol. Sci., November 1, 2005; 88(1): 150 - 160. [Abstract] [Full Text] [PDF]

				C. C. Dong, X. J. Yin, J. Y. C. Ma, L. Millecchia, Z.-X. Wu, M. W. Barger, J. R. Roberts, J. M. Antonini, R. D. Dey, and J. K. H. Ma Effect of Diesel Exhaust Particles on Allergic Reactions and Airway Responsiveness in Ovalbumin-Sensitized Brown Norway Rats Toxicol. Sci., November 1, 2005; 88(1): 202 - 212. [Abstract] [Full Text] [PDF]

				C. M. Prado, E. A. Leick-Maldonado, D. I. Kasahara, V. L. Capelozzi, M. A. Martins, and I. F. L. C. Tiberio Effects of acute and chronic nitric oxide inhibition in an experimental model of chronic pulmonary allergic inflammation in guinea pigs Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L677 - L683. [Abstract] [Full Text] [PDF]

				R. Morita, T. Uchiyama, and T. Hori Nitric Oxide Inhibits IFN-{alpha} Production of Human Plasmacytoid Dendritic Cells Partly via a Guanosine 3',5'-Cyclic Monophosphate-Dependent Pathway J. Immunol., July 15, 2005; 175(2): 806 - 812. [Abstract] [Full Text] [PDF]

				C. M. Prado, E. A. Leick-Maldonado, V. Arata, D. I. Kasahara, M. A. Martins, and I. F. L. C. Tiberio Neurokinins and inflammatory cell iNOS expression in guinea pigs with chronic allergic airway inflammation Am J Physiol Lung Cell Mol Physiol, April 1, 2005; 288(4): L741 - L748. [Abstract] [Full Text] [PDF]

				P. Keshavan, T. L. Deem, S. J. Schwemberger, G. F. Babcock, J. M. Cook-Mills, and S. D. Zucker Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration J. Immunol., March 15, 2005; 174(6): 3709 - 3718. [Abstract] [Full Text] [PDF]

				G. C. Koo, K. Shah, G. J. F. Ding, J. Xiao, R. Wnek, G. Doherty, X. C. Tong, R. B. Pepinsky, K.-C. Lin, W. K. Hagmann, et al. A Small Molecule Very Late Antigen-4 Antagonist Can Inhibit Ovalbumin-induced Lung Inflammation Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1400 - 1409. [Abstract] [Full Text] [PDF]

				M. A. Birrell, K. McCluskie, E.-B. Haddad, C. H. Battram, S. E. Webber, M. L. Foster, M. H. Yacoub, and M. G. Belvisi Pharmacological Assessment of the Nitric-Oxide Synthase Isoform Involved in Eosinophilic Inflammation in a Rat Model of Sephadex-Induced Airway Inflammation J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1285 - 1291. [Abstract] [Full Text] [PDF]

				P. R. Eynott, N. Paavolainen, D. A. Groneberg, A. Noble, M. Salmon, P. Nath, S.-Y. Leung, and K. F. Chung Role of Nitric Oxide in Chronic Allergen-Induced Airway Cell Proliferation and Inflammation J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 22 - 29. [Abstract] [Full Text] [PDF]

				A. Koarai, M. Ichinose, H. Sugiura, M. Tomaki, M. Watanabe, S. Yamagata, Y. Komaki, K. Shirato, and T. Hattori iNOS depletion completely diminishes reactive nitrogen-species formation after an allergic response Eur. Respir. J., September 1, 2002; 20(3): 609 - 616. [Abstract] [Full Text] [PDF]

				M. Feletou, M. Lonchampt, F. Coge, J.-P. Galizzi, C. Bassoullet, C. Merial, P. Robineau, J. A. Boutin, P. L. Huang, P. M. Vanhoutte, et al. Regulation of murine airway responsiveness by endothelial nitric oxide synthase Am J Physiol Lung Cell Mol Physiol, July 1, 2001; 281(1): L258 - L267. [Abstract] [Full Text] [PDF]

				H. Kobayashi, R. Hataishi, H. Mitsufuji, M. Tanaka, M. Jacobson, T. Tomita, W. M. Zapol, and R. C. Jones Antiinflammatory Properties of Inducible Nitric Oxide Synthase in Acute Hyperoxic Lung Injury Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 390 - 397. [Abstract] [Full Text]

				H. IIJIMA, A. DUGUET, S.-Y. EUM, Q. HAMID, and D. H. EIDELMAN Nitric Oxide and Protein Nitration are Eosinophil Dependent in Allergen-Challenged Mice Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1233 - 1240. [Abstract] [Full Text]

				K. A. Nath, V. Shah, J. J. Haggard, A. J. Croatt, L. A. Smith, R. P. Hebbel, and Z. S. Katusic Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R1949 - R1955. [Abstract] [Full Text] [PDF]

				A. Trifilieff, Y. Fujitani, F. Mentz, B. Dugas, M. Fuentes, and C. Bertrand Inducible Nitric Oxide Synthase Inhibitors Suppress Airway Inflammation in Mice Through Down-Regulation of Chemokine Expression J. Immunol., August 1, 2000; 165(3): 1526 - 1533. [Abstract] [Full Text] [PDF]

				H. SUGIURA, M. ICHINOSE, T. OYAKE, Y. MASHITO, Y. OHUCHI, N. ENDOH, M. MIURA, S. YAMAGATA, A. KOARAI, T. AKAIKE, et al. Role of Peroxynitrite in Airway Microvascular Hyperpermeability during Late Allergic Phase in Guinea Pigs Am. J. Respir. Crit. Care Med., August 1, 1999; 160(2): 663 - 671. [Abstract] [Full Text]

				M. A. Giembycz and M. A. Lindsay Pharmacology of the Eosinophil Pharmacol. Rev., June 1, 1999; 51(2): 213 - 340. [Abstract] [Full Text] [PDF]

				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]

				W. S. Cruz, J. A. Corbett, W. J. Longmore, and M. A. Moxley Nitric oxide participates in early events associated with NNMU-induced acute lung injury in rats Am J Physiol Lung Cell Mol Physiol, February 1, 1999; 276(2): L263 - L268. [Abstract] [Full Text] [PDF]

				Y. Xiong, G. Karupiah, S. P. Hogan, P. S. Foster, and A. J. Ramsay Inhibition of Allergic Airway Inflammation in Mice Lacking Nitric Oxide Synthase 2 J. Immunol., January 1, 1999; 162(1): 445 - 452. [Abstract] [Full Text] [PDF]

				C. M. Hogaboam, C. S. Gallinat, C. Bone-Larson, S. W. Chensue, N. W. Lukacs, R. M. Strieter, and S. L. Kunkel Collagen Deposition in a Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition Am. J. Pathol., December 1, 1998; 153(6): 1861 - 1872. [Abstract] [Full Text] [PDF]

				C. L. Hofstra, I. Van Ark, G. Hofman, F. P. Nijkamp, P. M. Jardieu, and A. J. M. Van Oosterhout Differential Effects of Endogenous and Exogenous Interferon-gamma on Immunoglobulin E, Cellular Infiltration, and Airway Responsiveness in a Murine Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., November 1, 1998; 19(5): 826 - 835. [Abstract] [Full Text]

				D. Stelts, R. W. Egan, A. Falcone, C. G. Garlisi, G. J. Gleich, W. Kreutner, T. T. Kung, D. K. Nahrebne, R. W. Chapman, and M. Minnicozzi Eosinophils Retain Their Granule Major Basic Protein in a Murine Model of Allergic Pulmonary Inflammation Am. J. Respir. Cell Mol. Biol., April 1, 1998; 18(4): 463 - 470. [Abstract] [Full Text]