The role of P-selectin and ICAM-1 in acute lung injury as determined using blocking antibodies and mutant mice.
Cobra venom factor (CVF) induces lung injury through oxidant- and neutrophil-dependent mechanisms. Adhesion molecules, particularly L-selectin, P-selectin, CD11/CD18, and ICAM-1, are required for full expression of injury in rats. This study compared the roles of P-selectin and ICAM-1 using either mutant mice or blocking Abs. Mice deficient in either P-selectin, ICAM-1, or both adhesion molecules were compared with wild-type mice. Wild-type and single mutant mice were given Abs against murine P-selectin or ICAM-1. CVF was injected i.v., and neutrophil sequestration and extravascular albumin were measured 30 min later. Neither P-selectin, ICAM-1, nor P-selectin/ICAM-1 double mutants showed a reduction in neutrophil sequestration or lung injury when compared with wild-type mice. Anti-P-selectin Abs inhibited both sequestration and injury in wild-type mice by 57% and 60%, respectively, but had no effect in P-selectin mutants. Similar results were found using anti-ICAM-1 Ab in wild-type mice (78% inhibition of sequestration and 88% inhibition of injury) and ICAM-1 mutant mice (no reduction). These results suggest that the apparent role of these molecules in CVF-induced lung injury depends on the method used to block function. When studied using blocking Abs, both P-selectin and ICAM-1 were required for neutrophil sequestration and lung injury, while neither played a role singly or together when studied using mice with genetic deletions. Abs may inhibit neutrophil sequestration and lung injury through mechanisms other than simply adhesion blockade, or mutant mice may utilize alternative adhesion pathways.
Doerschuk
C M
CM
Herman B. Wells Center for Pediatric Research, Indianapolis, IN 46202, USA.
Quinlan
W M
WM
Doyle
N A
NA
Bullard
D C
DC
Vestweber
D
D
Jones
M L
ML
Takei
F
F
Ward
P A
PA
Beaudet
A L
AL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001667:Binding, Competitive / Q000276:immunology; D004546:Elapid Venoms / Q000633:toxicity; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D008171:Lung Diseases / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019007:P-Selectin / Q000235:genetics / Q000502:physiology* / Q000633:toxicity
D000911:Antibodies, Monoclonal; D004546:Elapid Venoms; D019007:P-Selectin; C016310:cobra venom factor; D018799:Intercellular Adhesion Molecule-1