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This study examines the effect of monoclonal antibody to very late activation antigen-4 (VLA-4) on IL5-induced airway hyperresponsiveness in vivo and eosinophil accumulation into guinea pig airways. IL5 has been shown to be important in the development of airway hyperresponsiveness and eosinophil accumulation in the guinea pig. Eosinophils, unlike neutrophils, express VLA-4 which mediates the adhesion to vascular cell adhesion molecule-1 on endothelial cells. Thus VLA-4 seems to be an important adhesion molecule in the infiltration of eosinophils from the vasculature into the airway tissue. In addition, it has been shown that IL5 activates VLA-4 on eosinophils to facilitate their adhesion. In the present study, IL5 (1 microg, twice on one day) or vehicle were administered intranasally. Monoclonal antibody (mAb) to VLA-4 (HP1/2) or the isotype-matched control mAb (1E6) were injected 1 hour before each IL5 or vehicle treatment at a dose of 2.5 mg/kg body weight. The next day in vivo bronchial reactivity, eosinophil number in bronchoalveolar lavage (BAL) fluid, and eosinophil peroxidase (EPO) activity in cell-free BAL fluid were determined. IL5 induces an increase in bronchial reactivity to histamine, which is associated with an accumulation of eosinophils into BAL fluid (control: 12 (5 to 42) x 10(5) cells and IL5: 69 (11 to 99) x 10(5) cells, p < 0.05) and an increase of 35% +/- 14% in EPO activity in cell-free BAL fluid. Intravenous administration of anti-VLA-4 mAb, but not of the control antibody, completely inhibits the bronchial hyperresponsiveness as well as the airway eosinophilia found after intraairway application of IL5. HP1/2 also suppresses the IL5-induced increase in EPO activity in cell-free BAL fluid. In conclusion, for the development of IL5-induced airway hyperresponsiveness in the guinea pig, the VLA-4-dependent infiltration and activation of eosinophils in the bronchial tissue seems to be essential.

The influence of 13-hydroxy-linoleic acid (13-HODE) on the pulmonary resistance and dynamic compliance of guinea pigs in vivo was determined. Intravenously administered histamine and methacholine caused dose-dependent increases in pulmonary resistance and dose-dependent decreases in dynamic compliance in anesthetized, spontaneously breathing guinea pigs. Inhalation of an aerosol containing 13-HODE (10 mumol/L) enhanced the increases in pulmonary resistance observed after administration of histamine or methacholine when compared with the respective control animals. The effect of 13-HODE on the increase in pulmonary resistance after administration of histamine was dose-dependent. An enhancement in the pulmonary resistance was already measured after treatment of guinea pigs with aerosols of solutions containing 0.1 mumol/L 13-HODE when compared with that of control animals. In contrast, the changes in dynamic compliance were not affected by 13-HODE. These results indicate that 13-HODE may play an important role in the induction of airway hyperresponsiveness in vivo when it is produced or released in significant amounts in the airways.