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Am J Physiol Lung Cell Mol Physiol. 2015 Mar 15;308(6):L503-10. doi: 10.1152/ajplung.00328.2014. Epub 2015 Jan 16.

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

Author information

1
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.
2
Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada;
3
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;
4
Faculty of Health and Behavioural Sciences, Division of Biomedical Sciences, Department of Health Sciences, Northern Ontario School of Medicine, Lakehead University, Ontario, Canada; and.
5
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.

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.

KEYWORDS:

chronic lung disease; nitric oxide; oxidative stress

PMID:
25595650
DOI:
10.1152/ajplung.00328.2014
[Indexed for MEDLINE]
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