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/mm2) was found reduced only in the VCAM-1-mAb-treated animals (215 +/- 53 cells/mm2), while it was enhanced in animals treated with PECAM-1 IgG (572 +/- 126 cells/mm2).


CONCLUSIONS
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.
Nolte
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D
Department of Oral and Maxillofacial Surgery-Regional Plastic Surgery, Knappschaftskrankenhaus Bochum-Langendreer, University of Bochum, Bochum, Germany. dirk.nolte@ruhr-uni-bochum.de
Kuebler
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WM
Muller
W A
WA
Wolff
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KD
Messmer
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D000818:Animals; D002448:Cell Adhesion; D002450:Cell Communication; D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000276:immunology / Q000502:physiology; D019446:Endotoxemia / Q000276:immunology* / Q000503:physiopathology; D007962:Leukocytes / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology*
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019010:Vascular Cell Adhesion Molecule-1; D009195:Peroxidase