Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma.
l-Arginine metabolism by the arginase and nitric oxide (NO) synthase (NOS) families of enzymes is important in NO production, and imbalances between these pathways contribute to airway hyperresponsiveness (AHR) in asthma. To investigate the role of arginase isozymes (ARG1 and ARG2) in AHR, we determined the protein expression of ARG1, ARG2, the NOS isozymes, and other proteins involved in l-arginine metabolism in lung tissues from asthma patients and in acute (3-wk) and chronic (12-wk) murine models of ovalbumin-induced airway inflammation. Expression of ARG1 was increased in human asthma, whereas ARG2, NOS isoforms, and the other l-arginine-related proteins (i.e., cationic amino acid transporters 1 and 2, agmatinase, and ornithine decarboxylase) were unchanged. In the acute murine model of allergic airway inflammation, augmentation of ARG1 expression was similarly the most dramatic change in protein expression. However, ARG2, NOS1, NOS2, and agmatinase were also increased, whereas NOS3 expression was decreased. Arginase inhibition in vivo with nebulized S-(2-boronoethyl)-l-cysteine attenuated the methacholine responsiveness of the central airways in mice from the acute model. Further investigations in the chronic murine model revealed an expression profile that more closely paralleled the human asthma samples: only ARG1 expression was significantly increased. Interestingly, in the chronic mouse model, which generates a remodeling phenotype, arginase inhibition attenuated methacholine responsiveness of the central and peripheral airways. The similarity in arginase expression between human asthma and the chronic model and the attenuation of AHR after in vivo treatment with an arginase inhibitor suggest the potential for therapeutic modification of arginase activity in asthma.
North
Michelle L
ML
Institutes of Medical Sciences, Dalla Lana School of Public Health, Faculty of Medicine, Ontario, Canada .
Khanna
Nivedita
N
Marsden
Philip A
PA
Grasemann
Hartmut
H
Scott
Jeremy A
JA
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001249:Asthma / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014512:Ureohydrolases / Q000378:metabolism; D055815:Young Adult
D009569:Nitric Oxide; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D014512:Ureohydrolases; C477631:ARG2 protein, human; D001119:Arginase; C019625:agmatinase