THE ASSOCIATION BETWEEN ALPHA(4)-INTEGRIN, P-SELECTIN, AND E-SELECTININ AN ALLERGIC MODEL OF INFLAMMATION

In this study, we examined the relationship between the endothelial se lectins (P-selectin and E-selectin) and whether they are critical for alpha(4)-integrin-dependent leukocyte recruitment in inflamed (late ph ase response), cremasteric postcapillary venules. Animals were systemi cally sensitized and 2 wk later challenged intrascrotally with chicken ovalbumin. Leukocyte rolling flux, adhesion, and emigration were asse ssed at baseline and 4 and 8 h postantigen challenge. There was a sign ificant increase in leukocyte rolling flux, adhesion, and emigration i n sensitized and challenged mice at both 4 and 8 h. At 8 h, the increa se in leukocyte rolling flux was similar to 50% inhibitable by an anti -alpha(4)-integrin antibody, 98% inhibitable by fucoidin (a selectin-b inding carbohydrate), and 100% inhibitable by an anti-P-selectin antib ody. P-selectin-deficient animals displayed no leukocyte rolling or ad hesion at 8 h after challenge. However, at 8 h there were many emigrat ed leukocytes in the perivascular space suggesting P-selectin-independ ent rolling at an earlier time point. Indeed, at 4 h postantigen chall enge in P-selectin-deficient mice, there was increased leukocyte rolli ng, adhesion, and emigration. The rolling in the P-selectin-deficient mice at 4 h was largely alpha(4)-integrin dependent. However, there wa s an essential E-selectin-dependent component inasmuch as an anti-E-se lectin antibody completely reversed the rolling, and in E-selectin and P-selectin double deficient mice rolling, adhesion and emigration wer e completely absent. These results illustrate that P-selectin underlie s all of the antigen-induced rolling with a brief transient contributi on from E-selectin in the P-selectin-deficient animals. Finally, the a ntigen-induced alpha(4)-integrin-mediated leukocyte recruitment is ent irely dependent upon endothelial selectins.