The therapeutic potential of drugs targeting the arginase pathway in asthma.

Arginine metabolism by arginases may be of importance in health and disease, either by competing with nitric oxide synthases for the common substrate or by the production of L-ornithine. L-ornithine serves as a precursor for L-proline and polyamines, which may be involved in tissue remodelling by promoting collagen synthesis and cell proliferation. Arginase activity potentiates airway reactivity by reducing the production of bronchodilatory nitric oxide. Increased arginase activity has been implicated in the development of allergen-induced airway hyper-responsiveness in experimental asthma. In addition, reduced L-arginine availability to inducible nitric oxide synthase by arginase may lead to an increased production of peroxynitrite, contributing to increased airway smooth muscle contractility, airway inflammation and cell damage in this disease. Recent studies demonstrate that the upregulation of arginase by T helper type 2 cytokines in lung tissue as well as in cultured airway fibroblasts indicates a possible role of the enzyme in airway re-modelling. These findings, in conjunction with human studies showing a role for arginase in acute asthma, open a new horizon for the therapeutic potential of drugs targeting the arginase pathway in asthma.