Endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine ameliorates lipopolysaccharide-induced airway inflammation and bronchial hyperreactivity in mice

Abstract

Objectives: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. ADMA concentrations are augmented in lung, plasma samples of asthmatics. It remains unclear whether the increased concentration of ADMA in airway inflammation contributes to the pathophysiology or acts as a protective mechanism. The objective of this study was to evaluate the effects of exogenous ADMA on airway inflammation in mice.

Methods: Ex vivo/in vivo airway inflammation models were used. Tracheal tissues, isolated from female Balb/c mice were incubated with lipopolysaccharide (LPS), ADMA, or LPS + ADMA for 4 days in tissue culture. Tracheal reactivity was evaluated afterward by agonist-induced contraction responses. Female Balb/c mice were applied i.n. LPS (0,1 mg/ml) to induce in vivo airway inflammation. ADMA (30 mg/kg) was administered by i.n. route 1 h before and 24 h after LPS application.

Key findings: I.n. ADMA application augmented lung ADMA levels, reduced nitrite levels in bronchoalveolar lavage (BAL) fluid, prevented bronchial hyperreactivity and airway inflammation. ADMA also prevented bronchial hyperreactivity when applied 15 min before methacholine nebulization during the assessment of airway function.

Conclusion: Exogenously applied ADMA may have protective effects in airway inflammation by limiting excessive nitric oxide (NO) production. Targeting the DDAH/ADMA/NOS pathway may provide a therapeutic approach for airway inflammation.

Keywords: airway inflammation; asymmetric dimethylarginine; bronchial hyperreactivity; lipopolysaccharide.