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 postcapil lary venules by the lipid mediators leukotriene B-4 (LTB(4)) or platel et-activating factor (PAF). Leukocyte-endothelial cell adhesion and sh ear rate were monitored in rat mesenteric venules during superfusion w ith either LTB(4) or PAF in the presence or absence of monoclonal anti bodies (MAbs) directed against either leukocyte (CD18, CD11b) or endot helial cell [intercellular adhesion molecule 1 (ICAM-1), E-selectin, P -selectin] adhesion glycoproteins. In untreated animals and in animals receiving a nonbinding control MAb, LTB(4) and PAF increased the numb er of both adherent (8- and 4-fold, respectively) and emigrated (14- a nd 8-fold, respectively) leukocytes, while reducing leukocyte rolling velocity (36 and 33%, respectively). The LTB(4)- and PAF-induced leuko cyte adherence and emigration were significantly attenuated by pretrea tment with MAbs directed against CD18, CD11b, ICAM-1, and E-selectin, but not P-selectin. The reduction in leukocyte rolling velocity induce d by LTB(4) was not affected by any of the MAbs; however, both P- and E-selectin MAbs significantly attenuated the reduction in leukocyte ro lling velocity elicited by PAF. The results of this study indicate tha t the leukocyte adherence and emigration induced by both LTB(4) and PA F are mediated by CD11b/CD18 on leukocytes and by ICAM-1 and E-selecti n on endothelial cells. The molecular determinant of leukocyte rolling appears to be mediator specific, with the selectins mediating the rol ling elicited by PAF.