Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation

Rationale: In a guinea pig model of allergic asthma, using perfused tracheal preparations ex vivo, we demonstrated that L-arginine limitation due to increased arginase activity underlies a deficiency of bronchodilating nitric oxide (NO) and airway hyperresponsiveness (AHR) after the allergen-induced early and late asthmatic reaction.Objectives: Using the same animal model, we investigated the acute effects of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) and of L-arginine on AHR after the early and late reaction in vivo. In addition, we investigated the protection of allergen-induced asthmatic reactions, AHR, and airway inflammation by pretreatment with the drug.Methods: Airway responsiveness to inhaled histamine was measured in permanently instrumented, freely moving guinea pigs sensitized to ovalbumin at 24 hours before allergen challenge and after the allergen-induced early and late asthmatic reactions by assessing histamine PC(100) (provocative concentration causing a 100% increase of pleural pressure) values.Measurements and Main Results: Inhaled ABH acutely reversed AHR to histamine after the early reaction from 4.77 +/- 0.56-fold to 2.04 +/- 0.34 fold (P <0.001), and a tendency to inhibition was observed after the late reaction (from 1.95 +/- 0.56-fold to 1.56 +/- 0.47-fold, P <0.10). Quantitatively similar results were obtained with inhaled L-arginine. Remarkably, after pretreatment with ABH a 33-fold higher dose of allergen was needed to induce airway obstruction (P <0.01). Consequently, ABH inhalation 0.5 hour before and 8 hours after allergen challenge protected against the allergen-induced early and late asthmatic reactions, AHR and inflammatory cell infiltration.Conclusions: Inhalation of ABH or L-arginine acutely reverses allergen-induced AHR after the early and late asthmatic reaction, presumably by attenuating arginase-induced substrate deficiency to NO synthase in the airways. Moreover, ABH considerably reduces the airway sensitivity to inhaled allergen and protects against allergen-induced bronchial obstructive reactions, AHR, and airway inflammation. This is the first in vivo study indicating that arginase inhibitors may have therapeutic potential in allergic asthma.