Asymmetric dimethylarginine induces oxidative and nitrosative stress in murine lung epithelial cells

Sandra M. Wells, Andrij Holian

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


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 (O2-), 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 O2- 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.

Original languageEnglish
Pages (from-to)520-528
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number5
StatePublished - May 2007


  • ADMA
  • Epithelial cells
  • LA-4 cells
  • NOS
  • Oxidative stress


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