Molecular determinants of lipid mediator-induced leukocyte adherence and emigration in rat mesenteric venules

The objective of this study was to identify the molecular determinants of leukocyte rolling, adherence, and emigration elicited in postcapillary venules by the lipid mediators leukotriene B4 (LTB4) or platelet-activating factor (PAF). Leukocyte-endothelial cell adhesion and shear rate were monitored in rat mesenteric venules during superfusion with either LTB4 or PAF in the presence or absence of monoclonal antibodies (MAbs) directed against either leukocyte (CD18, CD11b) or endothelial cell [intercellular adhesion molecule 1 (ICAM-1), E-selectin, P-selectin] adhesion glycoproteins. In untreated animals and in animals receiving a nonbinding control MAb, LTB4 and PAF increased the number of both adherent (8- and 4-fold, respectively) and emigrated (14- and 8-fold, respectively) leukocytes, while reducing leukocyte rolling velocity (36 and 33%, respectively). The LTB4- and PAF-induced leukocyte adherence and emigration were significantly attenuated by pretreatment with MAbs directed against CD18, CD11b, ICAM-1, and E-selectin, but not P-selectin. The reduction in leukocyte rolling velocity induced by LTB4 was not affected by any of the MAbs; however, both P- and E-selectin MAbs significantly attenuated the reduction in leukocyte rolling velocity elicited by PAF. The results of this study indicate that the leukocyte adherence and emigration induced by both LTB4 and PAF are mediated by CD11b/CD18 on leukocytes and by ICAM-1 and E-selectin on endothelial cells. The molecular determinant of leukocyte rolling appears to be mediator specific, with the selectins mediating the rolling elicited by PAF.