Attenuation of leukocyte sequestration by selective blockade of PECAM-1 or VCAM-1 in murine endotoxemia

Background: Molecular mechanisms regulating leukocyte sequestration
into the tissue during endotoxemia and/or sepsis are still poorly
understood. This in vivo study investigates the biological role of
murine PECAM-1 and VCAM-1 for leukocyte sequestration into the
lung, liver and striated skin muscle. Methods: Male BALB/c mice
were injected intravenously with murine PECAM-1 IgG chimera or
monoclonal antibody (mAb) to VCAM-1 ( 3 mg/kg body weight);
controls received equivalent doses of IgG2a ( n = 6 per group).
Fifteen minutes thereafter, 2 mg/kg body weight of Salmonella
abortus equi endotoxin was injected intravenously. At 24 h after
the endotoxin challenge, lungs, livers and striated muscle of skin
were analyzed for their myeloperoxidase activity. To monitor
intravital leukocyte-endothelial cell interactions, fluorescence
videomicroscopy was performed in the skin fold chamber model of the
BALB/c mouse at 3, 8 and 24 h after injection of endotoxin.
Results: Myeloperoxidase activity at 24 h after the endotoxin
challenge in lungs (12,171 +/- 2,357 mU/g tissue), livers ( 2,204
+/- 238 mU/g) and striated muscle of the skin ( 1,161 +/- 110 mU/g)
was significantly reduced in both treatment groups as compared to
controls, with strongest attenuation in the PECAM-1 IgG treatment
group. Arteriolar leukocyte sticking at 3 h after endotoxin (230
+/- 46 cells x mm(-2)) was significantly reduced in both treatment
groups. Leukocyte sticking in postcapillary venules at 8 h after
endotoxin ( 343 +/- 69 cells/mm(2)) was found reduced only in the
VCAM-1-mAb-treated animals ( 215 +/- 53 cells/mm(2)), while it was
enhanced in animals treated with PECAM-1 IgG ( 572 +/- 126
cells/mm(2)). Conclusion: These data show that both PECAM-1 and
VCAM-1 are involved in endotoxin-induced leukocyte sequestration in
the lung, liver and muscle, presumably through interference with
arteriolar and/or venular leukocyte sticking. Copyright (C) 2004 S.
Karger AG, Basel.