Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness.
For many years it has been supposed that the production of an excess of nitric oxide (NO) by inducible NO synthase (iNOS) plays a major role in inflammatory diseases, including asthma. However, recent studies indicate that a deficiency of beneficial, bronchodilating constitutive NOS (cNOS)-derived NO is important in allergen-induced airway hyperresponsiveness. Although several mechanisms are proposed to explain the reduction of cNOS activity, reduced substrate availability, caused by a combination of increased arginase activity and decreased cellular uptake of L-arginine, appears to play a key role. Recent evidence also indicates that iNOS-induced pathophysiological effects involve substrate deficiency. Thus, at low concentrations of L-arginine iNOS produces both NO and superoxide anions, which results in the increased synthesis of the highly reactive, detrimental oxidant peroxynitrite. Based on these observations, we propose that a relative deficiency of NO caused by increased arginase activity and altered L-arginine homeostasis is a major factor in the pathology of asthma.
Meurs
Herman
H
Department of Molecular Pharmacology, University Centre for Pharmacy, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. h.meurs@farm.rug.nl
Maarsingh
Harm
H
Zaagsma
Johan
J
D000818:Animals; D001119:Arginase / Q000502:physiology*; D001249:Asthma / Q000201:enzymology* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D017942:Nitric Acid / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism
D007527:Isoenzymes; D017942:Nitric Acid; D019001:Nitric Oxide Synthase; D001119:Arginase; D009584:Nitrogen