Arginase Inhibition Prevents Inflammation and Remodeling in a Guinea Pig Model of Chronic Obstructive Pulmonary Disease

T. Pera*, A. B. Zuidhof, M. Smit, M. H. Menzen, T. Klein, G. Flik, J. Zaagsma, H. Meurs, H. Maarsingh

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Scopus)

Abstract

Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased L-ornithine/L-arginine and L-ornithine/L-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

Original languageEnglish
Pages (from-to)229-238
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume349
Issue number2
DOIs
Publication statusPublished - May-2014

Keywords

  • NITRIC-OXIDE SYNTHASE
  • BLEOMYCIN-INDUCED FIBROSIS
  • CIGARETTE-SMOKE
  • GENE-EXPRESSION
  • AIRWAY HYPERRESPONSIVENESS
  • ARGININOSUCCINATE SYNTHETASE
  • DEPENDENT MECHANISM
  • ARGININE METABOLISM
  • ENDOTHELIAL-CELLS
  • ALLERGIC-ASTHMA

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