Airway remodelling, characterized 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 inhitibor 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-sensitized 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 last 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 IL-13, whereas an increased L-ornithine/L-citrulline ratio in the lung was normalized. 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: Maarsingh H, Dekkers BG, Zuidhof AB, Bos IS, Menzen MH, Klein T, Flik G, Zaagsma J, Meurs H
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