Allergen‐induced airway constriction in guinea pig lung slices is attenuated by arginase inhibition via increased nitric oxide production

Abstract

In a guinea pig model of allergic asthma, arginase inhibition protects against allergen‐induced airway obstruction and greatly (>30‐fold) reduces airway sensitivity towards the inhaled allergen. Since arginase regulates nitric oxide (NO) synthesis via competition with NO synthase (NOS) for the common substrate L‐arginine, we hypothesized that the anti‐allergic effect of arginase inhibition involves increased NO synthesis. Ovalbumin (OVA; 0.0001–100 μg/ml)‐induced airway constriction was measured in lung slices obtained from actively‐sensitized guinea pigs using video‐assisted microscopy, in the absence or presence of inhibitors of arginase (ABH, 1μM or nor‐NOHA, 5 μM) and/or NOS (L‐NAME, 100 μM). OVA induced a dose‐dependent airway constriction with a mean maximal effect (Emax) of 98% and a mean EC50 of 0.039 μg/ml. ABH significantly reduced the Emax of OVA to 50%, whereas the sensitivity towards OVA was reduced by >100‐fold, to 5 μg/ml. nor‐NOHA mimicked the effects of ABH, whereas L‐NAME slightly increased contractile responses towards OVA (Emax: 100%; EC50: 0.007 μg/ml). L‐NAME partially reversed the protective effect of ABH against OVA (Emax: 74%; EC50: 0.125 μg/ml). In conclusion, arginase inhibition reduces allergen‐induced contractile responses of intrapulmonary airways by increasing NO synthesis.Supported by Erasmus Mundus partnership Join EU‐SEE and NIH grant HL‐103405.