title: Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.
abstract: Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension.
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; hartmut.grasemann@sickkids.ca.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada;
authors.forename: Rupinder
authors.initials: R
authors.lastname: Dhaliwal
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada;
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanovska
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada;
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada;
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.affiliation: Faculty of Health and Behavioural Sciences, Division of Biomedical Sciences, Department of Health Sciences, Northern Ontario School of Medicine, Lakehead University, Ontario, Canada; and.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Scott
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada;
authors.forename: Jaques
authors.initials: J
authors.lastname: Belik
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D000614:Aminocaproates / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology*; D001997:Bronchopulmonary Dysplasia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: C121228:2-amino-6-boronohexanoic acid; D000614:Aminocaproates; D000903:Antibiotics, Antineoplastic; D001896:Boron Compounds; D001761:Bleomycin; D009569:Nitric Oxide; D003094:Collagen; D001120:Arginine; D001119:Arginase
keywords: chronic lung disease; nitric oxide; oxidative stress