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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/L911    most recent 00025.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by North, M. L. Articles by Scott, J. A. PubMed PubMed Citation Articles by North, M. L. Articles by Scott, J. A.

Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma

¹Institutes of Medical Sciences and ⁶Occupational and Environmental Health Program, Dalla Lana School of Public Health, Faculty of Medicine, ²Divisions of Occupational and Respiratory Medicine and ⁴Nephrology, Department and Faculty of Medicine, and ⁵Physiology and Experimental Medicine and Division of Respiratory Medicine, The Hospital for Sick Children, University of Toronto; and ³Keenan Research Centre, Li Ka Shing Knowledge Institute and Gage Occupational and Environmental Health Unit, St. Michael's Hospital Research Centre, Toronto, Ontario, Canada

Submitted 23 January 2009 ; accepted in final form 12 March 2009

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.

S-(2-boronoethyl)-L-cysteine; agmatinase; nitric oxide