REDUCTION OF LEUKOCYTE ADHERENCE AND EMIGRATION BY CYCLOSPORINE AND L683,590 (FK506) IN POSTCAPILLARY VENULES

Although the actions of immunosuppressive agents on lymphocytes are well characterized, their influence on leukocyte-endothelial cell adhesive interactions has not been defined. The objective of this study was to determine whether cyclosporine and L-683,590 (FK520) could modify the adhesion and emigration of leukocytes in postcapillary venules that are exposed to inflammatory mediators such as platelet activating factor (PAF) and leukotriene B4 (LTB4). The rat mesentery was prepared for in vivo microscopic observation. Venules with internal diameters ranging between 25 mum and 35 mum were selected for study. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for >30 sec) and emigrated leukocytes were measured during superfusion of the mesentery with bicarbonate-buffered saline. Repeat measurements of adhesive and hemodynamic parameters were obtained between 50 and 60 min of superfusion with either 100 nM PAF or 20 nM LTB4 added to bicarbonate-buffered saline. In some experiments, animals were treated with either cyclosporine or L-683,590. Both PAF and LTB4 caused increases in leukocyte adherence and emigration, and reductions in leukocyte rolling velocity and venular shear rate. Cyclosporine prevented all of the adhesive and hemodynamic alterations induced by PAF, but not LTB4. L-683,590 was effective in preventing the responses elicited by both PAF and LTB4. These results indicate that modulation of leukocyte-endothelial cell adhesive interactions may represent a novel mechanism of action for cyclosporine and L-683,590.