Attenuation of Inhaled Allergen-induced Airway Microvascular Leakage and Airflow Obstruction in Guinea Pigs by a 5-Lipoxygenase Inhibitor (A-63162)

Abstract

Leukotrienes, products of the 5-lipoxygenase pathway in the metabolism of arachidonic acid, are potent mediators of airway microvascular leakage and smooth muscle contraction in guinea pigs. We studied the effect of a specific 5-lipoxygenase inhibitor, A-63162, on airway microvascular leakage and airflow obstruction following inhaled ovalbumin in actively sensitized guinea pigs. Airway microvascular leakage was assessed by extravasation of Evans blue dye into airway tissues. Inhaled ovalbumin caused increased lung resistance (RL) with decreased dynamic compliance (CL) and increased extravasation of Evans blue dye at all airway levels. A-63162 reduced the changes in RL and CL at 1.0 mumol/kg (p less than 0.05) but not at lower doses of 0.1 and 0.3 mumol/kg. A-63162 reduced Evans blue dye extravasation in airway tissues at all three doses, however, being most effective in the distal airways (p less than 0.01), and these reductions were greater than those in RL and CL. A 5-lipoxygenase inhibitor thus reduced airway microvascular leakage to a greater extent than airflow obstruction, suggesting that leukotrienes have a larger contribution to changes in airway microvascular permeability than smooth muscle contraction following inhaled allergen challenge in actively sensitized guinea pigs in vivo.