Human eotaxin induces eosinophil extravasation through rat mesenteric venules: role of alpha(4) integrins and vascular cell adhesion molecule-1

Eotaxin is a potent eosinophil-specific CC-chemokine, which has been shown to play a role in the selective induction of eosinophil accumulation in a n umber of allergic models of inflammation. Many aspects of the mechanism by which eotaxin induces eosinophil accumulation in vivo remain unresolved. In the present study, we investigated the direct effect of synthetic human eo taxin on leucocyte/endothelial cell interactions within rat mesenteric venu les, as quantified by intravital microscopy. Topical eotaxin (30 pmol) indu ced rapid firm adhesion and extravasation of leucocytes within the rat mese ntery, the extravasated leucocytes all being eosinophils, as determined by histological analysis. Whilst eotaxin was unable to stimulate the interacti on of rat eosinophils with vascular cell adhesion molecule-1 (VCAM-1) under static conditions in vitro, eotaxin-induced responses in vivo were signifi cantly suppressed by anti-alpha(4), integrin and anti-VCAM-1 monoclonal ant ibodies (mAbs). The anti-alpha(4), integrin mAb, HP2/1 (3.5 mg/kg), inhibit ed the eotaxin-induced firm adhesion and extravasation, 60 min postapplicat ion of the chemokine, by 89% and 84%, respectively. In the same set of expe riments, the anli-VCAM-1 mAb, 5F10 (3.5 mg/kg), inhibited leucocyte adhesio n and extravasation by 61% and 63%, respectively. These results demonstrate that eotaxin-induced migration of eosinophils through rat mesenteric venul es in vivo is dependent on an alpha(4), integrin/VCAM-1 adhesion pathway, t he significance of which may only be evident under flow conditions and/or f ollowing the ligation of other adhesion molecules expressed on eosinophils.