Title: Inhibition of nitric oxide restores surfactant gene expression following nickel-induced acute lung injury.
Authors: McDowell, Susan A; Gammon, Kelly; Zingarelli, Basilia; Bachurski, Cindy J; Aronow, Bruce J; Prows, Daniel R; Leikauf, George D
Published In Am J Respir Cell Mol Biol, (2003 Feb)
Abstract: 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, N(G)-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-gamma, interleukins-1beta and -6, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) 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.
PubMed ID: 12540486
MeSH Terms: Animals; Bronchoalveolar Lavage Fluid/chemistry; Bronchoalveolar Lavage Fluid/cytology; Cytokines/genetics; Enzyme Inhibitors/pharmacology; Gene Expression/drug effects; Lung/drug effects*; Lung/injuries; Lung/metabolism*; Mice; Mice, Inbred A; NG-Nitroarginine Methyl Ester/pharmacology; Neutrophils/drug effects; Nickel/toxicity*; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitric Oxide Synthase/antagonists & inhibitors; Nitric Oxide/antagonists & inhibitors*; Pulmonary Surfactant-Associated Protein A/genetics; Pulmonary Surfactant-Associated Protein B/genetics; Pulmonary Surfactant-Associated Protein C/genetics; Pulmonary Surfactants/metabolism*; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.