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*
BHF Cardiovascular Medicine Unit, Imperial College School of Medicine at the National Heart and Lung Institute, Hammersmith Hospital;
Electron Microscopy Unit, Royal Brompton and Harefield National Health Service Trust; and
University College London Medical School, London, United Kingdom; and
§
Centocor, Malvern, PA, 19355
The final stage in the migration of leukocytes to sites of
inflammation involves movement of leukocytes through the endothelial
cell layer and the perivascular basement membrane. Both
platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) and the
integrin 
vß3 have been implicated in this
process, and in vitro studies have identified
vß3 as a heterotypic ligand for PECAM-1.
In the present study we have addressed the roles of these molecules by
investigating and comparing the effects of PECAM-1 and
vß3 blockade on leukocyte migration in
vivo. For this purpose we have examined the effects of neutralizing Abs
directed against PECAM-1 (domain 1-specific, mAb 37) and
ß3 integrins (mAbs 7E3 and F11) on leukocyte responses in
the mesenteric microcirculation of anesthetized rats using intravital
microscopy. The anti-PECAM-1 mAb suppressed leukocyte
extravasation, but not leukocyte rolling or firm adhesion, elicited by
IL-1ß in a dose-dependent manner (e.g., 67% inhibition at 10 mg/kg
37 Fab), but had no effect on FMLP-induced leukocyte responses.
Analysis by electron microscopy suggested that this suppression was due
to an inhibition of neutrophil migration through the endothelial cell
barrier. By contrast, both anti-ß3 integrin mAbs, 7E3
F(ab')2 (5 mg/kg) and F11 F(ab')2 (5 mg/kg),
selectively reduced leukocyte extravasation induced by FMLP (38 and
46%, respectively), but neither mAb had an effect on IL-1ß-induced
leukocyte responses. These findings indicate roles for both PECAM-1 and
ß3 integrins in leukocyte extravasation, but do not
support the concept that these molecules act as counter-receptors in
mediating leukocyte transmigration.
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