Arginase in Asthma - Recent Developments in Animal and Human Studies

ABSTRACT

The enzyme, arginase, converts L-arginine into L-ornithine and urea, and has been implicated in the pathogenesis of lung diseases, related to dysregulation of L-arginine metabolism and remodeling. Allergic asthma is a chronic condition characterized by inflammation, lung remodeling and airways hyperresponsiveness (AHR). Increased expression of arginase may contribute to AHR in asthma by reducing L-arginine bioavailability for the nitric oxide synthase (NOS) isozymes, thus, limiting the production of the endogenous bronchodilator, nitric oxide (NO). Reduction of intracellular L-arginine concentrations as a consequence of augmented arginase expression and activity may also promote NOS uncoupling, resulting in increased formation of peroxynitrite, a powerful oxidant that promotes bronchoconstriction and inflammation. In chronic asthma, increased arginase expression may also contribute to airways remodeling, through increased synthesis of L-ornithine, and hence the production of polyamines and L-proline, which are involved in cell proliferation and collagen deposition, respectively. New drugs targeting the arginase pathway could have therapeutic benefits in asthma. This review focuses on recent developments in our understanding of the role of arginase in AHR, inflammation and remodeling, highlighting studies that advance our knowledge of L-arginine dysregulation in human asthma and animal studies that explore the therapeutic potential of arginase inhibition.

Keywords:

Nitric oxide, L-arginine, Airways remodeling, inflammation, airway hyperresponsiveness, polyamines, fibrosis, proline, peroxynitrite.