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 neut rophil-dependent mechanisms. Adhesion molecules, particularly L-select in, P-selectin, CD11/CD18, and ICAM-1, are required for full expressio n of injury in rats. This study compared the roles of P-selectin and I CAM-1 using either mutant mice or blocking Abs, Mice deficient in eith er P-selectin, ICAM-1, or both adhesion molecules were compared with w ild-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 se questration and extravascular albumin were measured 30 min later. Neit her P-selectin, ICAM-1, nor P-selectin/ICAM-1 double mutants showed a reduction in neutrophil sequestration or lung injury when compared wit h wild-type mice. Anti-P-selectin Abs inhibited both sequestration and injury in wild-type mice by 57% and 60%, respectively, but had no eff ect in P-selectin mutants, Similar results were found using anti-ICAM- 1 Ab in wild-type mice (78% inhibition of sequestration and 88% inhibi tion of injury) and ICAM-1 mutant mice (no reduction), These results s uggest that the apparent role of these molecules in CVF-induced lung i njury 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 inhib it neutrophil sequestration and lung injury through mechanisms other t han simply adhesion blockade, or mutant mice may utilize alternative a dhesion pathways.