Figure 1.

Pathways of l‐arginine metabolism and their relationship to allergen‐induced airway obstruction, airway inflammation, airway hyperresponsiveness and airway remodeling, and enhanced allergen sensitivity. Nitric oxide (NO) is synthesized from l‐arginine by constitutive and inducible NO synthases. NO has bronchodilatory and anti‐inflammatory actions and inhibits mediator release from mast cells. l‐Arginine is also metabolized to l‐ornithine and urea by arginases 1 and 2. Th2 cytokines (IL‐4 and IL‐13) and TGF‐β induce increased arginase expression and activity, which reduces the availability of l‐arginine to the NO synthases. This reduces the production of NO and induces production of superoxide anion (${\text{O}}_2^{-}$) by these enzymes, causing formation of their reaction product peroxynitrite (ONOO ⁻), which has pro‐contractile and pro‐inflammatory actions in the airways. Collectively, these processes contribute to allergen‐induced airway obstruction, airway inflammation and airway hyperresponsiveness, and increased sensitivity to the allergen. Furthermore, the increased synthesis of l‐ornithine from arginase provides a precursor for polyamines and l‐proline, which stimulate cell proliferation, and collagen production and fibrosis, respectively, causing airway remodeling. IL‐4, interleukin‐4; IL‐13, interleukin‐13; NO, nitric oxide; ONOO ⁻, peroxynitrite; TGF‐β, transforming growth factor‐β [Color figure can be viewed at wileyonlinelibrary.com]