© 2003 American Thoracic Society DOI: 10.1165/rcmb.2002-0077OC Inhibition of Nitric Oxide Restores Surfactant Gene Expression following Nickel-Induced Acute Lung InjuryUniversity of Cincinnati; and Children's Hospital Medical Center, Cincinnati, Ohio Address correspondence to: George D. Leikauf, Ph.D., Department of Environmental Health, University of Cincinnati, P.O. Box 670056, Cincinnati, OH 45267-0056. E-mail: leikaugd{at}ucmail.uc.edu
The role of nitric oxide (NO) in acute lung injury remains controversial. Although inhaled NO increases oxygenation in clinical trials, inhibiting NO-synthase (NOS) can be protective. To examine the latter, nickel-exposed mice were treated with saline or NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Initial microarray analysis of nickel-induced gene expression of saline-treated mice revealed increased inflammatory mediator, matrix injury-repair, and hypoxia-induced factor-mediated sequences and decreased lung-specific (e.g., surfactant-associated protein B and C) sequences. Compared with saline control, L-NAME–treated mice had enhanced survival with attenuated serum nitrate/nitrite, endothelial NOS activity, and lavage neutrophils and protein. Although initial cytokine (i.e., interferon-
Abbreviations: Dulbecco's phosphate-buffered saline, D-PBS • endothelial NOS, eNOS • expressed sequence tag, EST • interferon, IFN • interleukin, IL • inducible NOS, iNOS • NG-nitro-L-arginine methyl ester, L-NAME • monocyte chemotactic protein, MCP • macrophage migration inhibitory factor, Mif • macrophage inflammatory protein, MIP • nitric oxide, NO • NO synthase, NOS • polymorphonuclear leukocyte, PMN • surfactant-associated protein, SP • tumor necrosis factor, TNF This article has been cited by other articles:
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, interleukins-1ß and -6, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and tumor necrosis factor-
) gene expression was similar between groups, subsequent larger cytokine increases only occurred in saline-treated mice. Similarly, surfactant protein gene expression decreased initially in both groups yet was restored subsequently with L-NAME treatment. Interestingly, the role of inducible NOS (iNOS) in these responses seems minimal. iNOS gene expression was unaltered, iNOS activity and nitrotyrosine residues were undetectable, and an iNOS antagonist, aminoguanidine, failed to increase survival. Rather, systemic L-NAME treatment appears to attenuate pulmonary endothelial NOS activity, subsequent cytokine expression, inflammation, and protein permeability, and thereby restores surfactant gene expression and increases survival. 
