title: Increased arginase activity contributes to airway remodelling in chronic allergic asthma.
abstract: Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and l-proline downstream of the arginase product l-ornithine, and via reduced nitric oxide synthesis. Using the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbumin-sensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge. Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased l-ornithine/l-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH. These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. h.maarsingh@rug.nl
authors.forename: H
authors.initials: H
authors.lastname: Maarsingh
authors.forename: B G J
authors.initials: BG
authors.lastname: Dekkers
authors.forename: A B
authors.initials: AB
authors.lastname: Zuidhof
authors.forename: I S T
authors.initials: IS
authors.lastname: Bos
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
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology*; D000485:Allergens / Q000009:adverse effects; D000614:Aminocaproates / Q000627:therapeutic use; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001119:Arginase / Q000037:antagonists & inhibitors / Q000502:physiology*; D001249:Asthma / Q000201:enzymology* / Q000503:physiopathology*; D001896:Boron Compounds / Q000627:therapeutic use; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D002908:Chronic Disease; D002956:Citrulline / Q000032:analysis; D004802:Eosinophilia / Q000188:drug therapy; D005088:Exocrine Glands / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects; D006168:Guinea Pigs; D018793:Interleukin-13 / Q000032:analysis; D008168:Lung / Q000737:chemistry; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects; D009952:Ornithine / Q000032:analysis; D010047:Ovalbumin / Q000009:adverse effects; D011658:Pulmonary Fibrosis / Q000188:drug therapy; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
chemical_list: C121228:2-amino-6-boronohexanoic acid; D000485:Allergens; D000614:Aminocaproates; D018927:Anti-Asthmatic Agents; D001896:Boron Compounds; D018793:Interleukin-13; D002956:Citrulline; D010047:Ovalbumin; D009952:Ornithine; D001119:Arginase