JG Mastronarde, MM Monick and GW Hunninghake
Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa College of Medicine, Iowa City, USA.

Respiratory syncytial virus (RSV) is an important respiratory pathogen that preferentially infects epithelial cells in the airway, and causes a local inflammatory response. Although it has been previously demonstrated that RSV-infected airway epithelial produce cytokines, including interleukin-8 (IL-8), which contributes to the inflammatory response, the regulation of this effect of RSV is unknown. To further characterize the mechanisms by which RSV infection triggers release of IL-8, we first exposed cultured A549 cells to RSV, and measured IL-8 release via enzyme-linked immunosorbent assays (ELISA), and IL-8 messenger RNA (mRNA) induction via Northern blot analysis. We observed a dose- and time-dependent release of IL-8 in response to RSV. The optimal dose of RSV was 10(4) TCID50/ml, and maximal release of IL-8 was measured at 72 to 96 h after infection. RSV induced a biphasic (early and late) increase in IL-8 mRNA. The early phase was independent of viral infection, whereas the more pronounced late phase required the presence of live virus and infection of the epithelium. Partial (< 50%) cytopathic effects were noted at 48 h and progressed to 75% at 96 h. The monolayer was still intact at 96 h. Inhibitors of nitric oxide, including NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME), and aminoguanidine had no effect on IL-8 release or IL- 8 mRNA induction. We did, however, demonstrate a dose-dependent decrease in IL-8 release and IL-8 mRNA induction in RSV-infected epithelial treated with the antioxidants dimethyl sulfoxide (DMSO) or 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Peak effects were noted at a concentration of 2% DMSO and 50 microM DMPO. The antioxidants did not inhibit viral replication or infection. This data suggest that RSV- induced IL-8 production in airway epithelium is mediated via changes in oxidant tone. The data also suggest a potential therapeutic role for antioxidants in RSV infections.

This article has been cited by other articles:

				K. Fink, A. Duval, A. Martel, A. Soucy-Faulkner, and N. Grandvaux Dual Role of NOX2 in Respiratory Syncytial Virus- and Sendai Virus-Induced Activation of NF-{kappa}B in Airway Epithelial Cells J. Immunol., May 15, 2008; 180(10): 6911 - 6922. [Abstract] [Full Text] [PDF]

				I. C. Davis, E. R. Lazarowski, F.-P. Chen, J. M. Hickman-Davis, W. M. Sullender, and S. Matalon Post-Infection A77-1726 Blocks Pathophysiologic Sequelae of Respiratory Syncytial Virus Infection Am. J. Respir. Cell Mol. Biol., October 1, 2007; 37(4): 379 - 386. [Abstract] [Full Text] [PDF]

				B. D. Rudd, E. Burstein, C. S. Duckett, X. Li, and N. W. Lukacs Differential Role for TLR3 in Respiratory Syncytial Virus-Induced Chemokine Expression J. Virol., March 15, 2005; 79(6): 3350 - 3357. [Abstract] [Full Text] [PDF]

				M. M. Monick, K. Cameron, J. Staber, L. S. Powers, T. O. Yarovinsky, J. G. Koland, and G. W. Hunninghake Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis J. Biol. Chem., January 21, 2005; 280(3): 2147 - 2158. [Abstract] [Full Text] [PDF]

				M. M. Monick, K. Cameron, L. S. Powers, N. S. Butler, D. McCoy, R. K. Mallampalli, and G. W. Hunninghake Sphingosine Kinase Mediates Activation of Extracellular Signal-Related Kinase and Akt by Respiratory Syncytial Virus Am. J. Respir. Cell Mol. Biol., June 1, 2004; 30(6): 844 - 852. [Abstract] [Full Text] [PDF]

				J. Li, S. Kartha, S. Iasvovskaia, A. Tan, R. K. Bhat, J. M. Manaligod, K. Page, A. R. Brasier, and M. B. Hershenson Regulation of human airway epithelial cell IL-8 expression by MAP kinases Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L690 - L699. [Abstract] [Full Text] [PDF]

				C. Zouki, L. József, S. Ouellet, Y. Paquette, and J. G. Filep Peroxynitrite mediates cytokine-induced IL-8 gene expression and production by human leukocytes J. Leukoc. Biol., May 1, 2001; 69(5): 815 - 824. [Abstract] [Full Text]

				P.A.B. Wark, S.L. Johnston, I. Moric, J.L. Simpson, M.J. Hensley, and P.G. Gibson Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma Eur. Respir. J., January 1, 2001; 19(1): 68 - 75. [Abstract] [Full Text] [PDF]

				M. W. Frampton, A. J. Ghio, J. M. Samet, J. L. Carson, J. D. Carter, and R. B. Devlin Effects of aqueous extracts of PM10 filters from the Utah Valley on human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 1999; 277(5): L960 - L967. [Abstract] [Full Text] [PDF]

				G. Gudmundsson, M. M. Monick, and G. W. Hunninghake Viral Infection Modulates Expression of Hypersensitivity Pneumonitis J. Immunol., June 15, 1999; 162(12): 7397 - 7401. [Abstract] [Full Text] [PDF]

				P. KAUL, I. SINGH, and R. B. TURNER Effect of Nitric Oxide on Rhinovirus Replication and Virus-Induced Interleukin-8 Elaboration Am. J. Respir. Crit. Care Med., April 1, 1999; 159(4): 1193 - 1198. [Abstract] [Full Text] [PDF]

				J. G. Filep, M. Beauchamp, C. Baron, and Y. Paquette Peroxynitrite Mediates IL-8 Gene Expression and Production in Lipopolysaccharide-Stimulated Human Whole Blood J. Immunol., November 15, 1998; 161(10): 5656 - 5662. [Abstract] [Full Text] [PDF]

				S. L. Johnston, A. Papi, P. J. Bates, J. G. Mastronarde, M. M. Monick, and G. W. Hunninghake Low Grade Rhinovirus Infection Induces a Prolonged Release of IL-8 in Pulmonary Epithelium J. Immunol., June 15, 1998; 160(12): 6172 - 6181. [Abstract] [Full Text] [PDF]

				I. Legastelois, H. Levrey, T. Greenland, J.-F. Mornex, and G. Cordier Visna-maedi Virus Induces Interleukin-8 in Sheep Alveolar Macrophages through a Tyrosine-kinase Signaling Pathway Am. J. Respir. Cell Mol. Biol., April 1, 1998; 18(4): 532 - 537. [Abstract] [Full Text]

				K. Knobil, A. M. K. Choi, G. W. Weigand, and D. B. Jacoby Role of oxidants in influenza virus-induced gene expression Am J Physiol Lung Cell Mol Physiol, January 1, 1998; 274(1): L134 - L142. [Abstract] [Full Text] [PDF]

				A. BLOMBERG, M. T. KRISHNA, V. BOCCHINO, G. L. BISCIONE, J. K. SHUTE, F. J. KELLY, A. J. FREW, S. T. HOLGATE, and T. SANDSTRÖM The Inflammatory Effects of 2 ppm NO2 on the Airways of Healthy Subjects Am. J. Respir. Crit. Care Med., July 1, 1997; 156(2): 418 - 424. [Abstract] [Full Text]

				A. Casola, N. Burger, T. Liu, M. Jamaluddin, A. R. Brasier, and R. P. Garofalo Oxidant Tone Regulates RANTES Gene Expression in Airway Epithelial Cells Infected with Respiratory Syncytial Virus. ROLE IN VIRAL-INDUCED INTERFERON REGULATORY FACTOR ACTIVATION J. Biol. Chem., June 1, 2001; 276(23): 19715 - 19722. [Abstract] [Full Text] [PDF]