title: Plasma arginine metabolites reflect airway dysfunction in a murine model of allergic airway inflammation.
abstract: L-arginine metabolism is important in the maintenance of airway tone. Shift of metabolism from the nitric oxide synthase to arginase pathways contributes to the increased airway responsiveness in asthma. We tested the hypothesis that systemic levels of L-arginine metabolites are biomarkers reflective of airway dysfunction. We used a mouse model of acute allergic airway inflammation to OVA that manifests with significant airway hyperresponsiveness to methacholine. To determine tissue arginase activity in vivo, the isotopic enrichment of an infused L-arginine stable isotope and its product amino acid L-ornithine were measured in lung and airway homogenates using liquid chromatography-tandem mass spectrometry. Tissue and plasma concentrations of other L-arginine metabolites, including L-citrulline and symmetric and asymmetric dimethylarginine, were measured and correlated with lung arginase activity and methacholine responsiveness of the airways. The effectiveness of intratracheal instillation of an arginase inhibitor (boronoethylcysteine) on pulmonary arginase activity and circulating concentrations of L-arginine metabolites was also studied. We demonstrate that 1) plasma indexes of L-arginine bioavailability and impairment of nitric oxide synthase function correlate with airway responsiveness to methacholine; 2) plasma levels of L-ornithine predict in vivo pulmonary arginase activity and airway function; and 3) acute arginase inhibition reduces in vivo pulmonary arginase activity to control levels and normalizes plasma L-ornithine, but not L-arginine, bioavailability in this model. We conclude that plasma L-ornithine may be useful as a systemic biomarker to predict responses to therapeutic interventions targeting airway arginase in asthma.
authors.affiliation: Department of Health Sciences, Faculty of Health and Behavioural Sciences, Lakehead University, and Division of Medical Sciences, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Dalla Lana School of Public Health, Division of Occupational and Environmental Health, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Scott
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Michelle L
authors.initials: ML
authors.lastname: North
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada;
authors.forename: Mahrouk
authors.initials: M
authors.lastname: Rafii
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada;
authors.forename: Hailu
authors.initials: H
authors.lastname: Huang
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada; Department of Pediatrics, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Pencharz
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada; Division of Respiratory Medicine, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada; and Department of Pediatrics, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario Canada hartmut.grasemann@sickkids.ca.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood*; D001249:Asthma / Q000097:blood* / Q000503:physiopathology*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002956:Citrulline / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009952:Ornithine / Q000097:blood; D010047:Ovalbumin; D012137:Respiratory System / Q000503:physiopathology*
chemical_list: D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; C487735:dimethylarginine; D016210:Methacholine Chloride; D002956:Citrulline; D010047:Ovalbumin; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D001119:Arginase
keywords: airway function; arginine metabolism; biomarker