Competitive metabolism of L-arginine:arginase as a therapeutic target in asthma

Exhaled breath nitric oxide (NO) is an accepted asthma biomarker.Lung concentrations of NO and its amino acid precursor,L-arginine,are regulated by the relative expressions of the NO synthase (NOS) and arginase isoforms.Increased expression of arginase I and NOS2 occurs in murine models of allergic asthma and in biopsies of asthmatic airways.Although clinical trials involving the inhibition of NO-producing enzymes have shown mixed results,small molecule arginase inhibitors have shown potential as a therapeutic intervention in animal and cell culture models.Their transition to clinical trials is hampered by concerns regarding their safety and potential toxicity.In this review,we discuss the paradigm of arginase and NOS competition for their substrate L-arginine in the asthmatic airway.We address the functional role of L-arginine in inflammation and the potential role of arginase inhibitors as therapeutics.