Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma

Elizabeth Klein, Jason Weigel, Mary C. Buford, Andrij Holian, Sandra M. Wells

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO), formed by nitric oxide synthase (NOS), is an important mediator of lung inflammation in allergic asthma. Asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of NOS, is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Elevated ADMA has been shown to affect lung function in mice, and by inhibiting NOS it alters NO and reactive oxygen species production in mouse lung epithelial cells. However, the effects of altered ADMA levels during lung inflammation have not been explored. A model of allergen-induced airway inflammation was utilized in combination with the modulation of endogenous circulating ADMA levels in mice. Airway inflammation was assessed by quantifying inflammatory cell infiltrates in lung lavage and by histology. Lung DDAH expression was assessed by quantitative PCR and immunohistochemistry. Nitrite levels were determined in lung lavage fluid as a measure of NO production. iNOS expression was determined by immunohistochemistry, immunofluorescence, Western blot, and quantitative PCR. NF-κB binding activity was assessed by a transcription factor binding assay. Allergen-induced lung inflammation was potentiated in mice with elevated circulating ADMA and was reduced in mice overexpressing DDAH. Elevated ADMA reduced nitrite levels in lung lavage fluid in both allergenchallenged and control animals. ADMA increased iNOS expression in airway epithelial cells in vivo following allergen challenge and in vitro in stimulated mouse lung epithelial cells. ADMA also increased NF-κB binding activity in airway epithelial cells in vitro. These data support that ADMA may play a role in inflammatory airway diseases such as asthma through modulation of iNOS expression in lung epithelial cells.

Original languageEnglish
Pages (from-to)L816-L825
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume299
Issue number6
DOIs
StatePublished - Dec 2010

Keywords

  • Airway
  • Dimethylarginine dimethylaminohydrolase
  • Inducible nitric oxide synthase

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