α₄ Integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice

We investigated the roles of eosinophil infiltration and activation induced by the cosinophil-selective chemokine eotaxin, and of the expression of eosinophil α₄ and β₂ integrins in causing bronchial hyperresponsiveness (BHR) in interleukin (IL)-5 CBA/Ca transgenic mice. These mice did not show BHR, despite the presence of some eosinophils in the lungs. Intratracheal mouse recombinant eotaxin (3 μg) did not induce BHR in wild-type mice. In IL-5 transgenic mice, eotaxin (3 and 5 μg) increased responsiveness at 24 h and increased cosinophils in bronchoalveolar lavage (BAL) fluid by 9,4- and 14-fold by 24 h, respectively, together with augmentation of eosinophil peroxidase activity and cosinophil infiltration in the airway submucosa. Using flow cytometry, the expression of α₄, CD11b, and CD18 was upregulated in BAL, but not in blood, eosinophils. A rat anti-α₄ antibody inhibited eotaxin-induced BHR and cosinophil migration and activation, but an anti-CD11b antibody had no significant effects on BHR. A combination of both antibodies was more effective. IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil α₄ integrin. Expression of BHR depends on the recruitment and activation of cosinophils.