title: Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease.
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.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands (T.P., A.B.Z., M.S., M.H.M., J.Z., H.Me., H.Ma.); and Brains On-Line BV, Groningen, The Netherlands (T.K., G.F.).
authors.forename: T
authors.initials: T
authors.lastname: Pera
authors.forename: A B
authors.initials: AB
authors.lastname: Zuidhof
authors.forename: M
authors.initials: M
authors.lastname: Smit
authors.forename: M H
authors.initials: MH
authors.lastname: Menzen
authors.forename: T
authors.initials: T
authors.lastname: Klein
authors.forename: G
authors.initials: G
authors.lastname: Flik
authors.forename: J
authors.initials: J
authors.lastname: Zaagsma
authors.forename: H
authors.initials: H
authors.lastname: Meurs
authors.forename: H
authors.initials: H
authors.lastname: Maarsingh
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005355:Fibrosis; D006168:Guinea Pigs; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D055271:Mucin 5AC / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology
chemical_list: D016209:Interleukin-8; D008070:Lipopolysaccharides; D055271:Mucin 5AC; D001119:Arginase