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Asymmetric Dimethylarginine Induces Oxidative and Nitrosative Stress in Murine Lung Epithelial Cells

Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana

Correspondence and requests for reprints should be addressed to Sandra Wells, Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Skaggs Building, Room 155, Missoula, MT 59812. E-mail: sandra.wells{at}umontana.edu

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by epithelial and inflammatory cells are key mediators of the chronic airway inflammation of asthma. Low L-arginine levels can result in the uncoupling of nitric oxide synthase (NOS) leading to production of both ROS and RNS. Asymmetric dimethylarginine (ADMA) is a competitive endogenous inhibitor of all NOS isoforms and has been demonstrated to inhibit NO formation and increase oxidative stress in vascular endothelial and smooth muscle cells. The effect of ADMA on inducible NOS (iNOS) activity in epithelial cells has not been explored. In this study, we investigated whether addition of exogenous ADMA alters the generation of NO and superoxide anion (), leading to peroxynitrite (ONOO^–) formation in a mouse epithelial cell line. In stimulated LA-4 cells, ADMA dose-dependently inhibited nitrite accumulation after 24 h of treatment. In addition, ADMA concentrations as low as 10 µM induced rapid increases in production as measured by dihydroethidium oxidation. Furthermore, using dihydrorhodamine to monitor ONOO^– formation, ADMA caused a dose-dependent increase in ONOO^– after treatment for 24 h. Similar effects of ADMA were seen using purified iNOS protein in a cell-free system. Together, these data indicate that elevated ADMA may contribute to the production of ROS and RNS in airway inflammation.

Key Words: ADMA • epithelial cells • LA-4 cells • NOS • oxidative stress

CLINICAL RELEVANCE This study demonstrates that elevated levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) may contribute to the production of reactive oxygen species and reactive nitrogen species in airway inflammation. These findings suggest that ADMA may play a role in airway diseases including asthma.

 

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