LEUKOTRIENE C-4/D-4 INDUCES P-SELECTIN AND SIALYL LEWIS(X)-DEPENDENT ALTERATIONS IN LEUKOCYTE KINETICS IN-VIVO

The objective of this study was to assess the effect of leukotriene C-4 (LTC(4)) on the flux of rolling leukocytes, rolling leukocyte velocity, and leukocyte adhesion in postcapillary venules in vivo and to study the underlying molecular mechanisms involved. LTC(4) (20 nmol/L) induced a rapid and significant increase in leukocyte rolling flux that was inhibitable by an anti-P-selectin antibody and soluble sialyl Lewis(x) (sLe(x)). LTC(4) also induced a significant reduction in leukocyte rolling velocity, an event that was independent of P-selectin but entirely dependent on sLe(x). This LTC(4)-induced reduction in leukocyte rolling velocity was independent of any hemodynamic alterations. Another P-selectin effector, histamine, did not affect leukocyte rolling velocity even at greater than 5000 times the concentration of LTC(4). Treatment with an anti-L-selectin antibody had no effect on the LTC(4)-induced increase in leukocyte rolling or reduction in rolling velocity. Inhibition of LTC(4) bioconversion to LTD(4) by pretreatment with L-serine (100 mu-mol/L) prevented the LTC(4)-induced increase in leukocyte rolling flux and the LTC(4)-induced reduction in leukocyte rolling velocity. A subtle, yet significant, increase in leukocyte adhesion was also observed with LTC(4). Pretreatment with a platelet-activating factor receptor antagonist returned the LTC(4)-induced leukocyte rolling velocity to baseline levels. The addition of a very low concentration of platelet-activating factor (1 nmol/L) induced significant leukocyte adhesion in the presence of LTC(4) but not histamine. This study demonstrates that LTC(4), via bioconversion to leukotriene D-4, induces a P-selectin-dependent and sLe(x)-dependent increase in leukocyte rolling flux and a P-selectin-independent but sLe(x)-dependent reduction in leukocyte rolling velocity, a parameter that may play an essential role in subsequent leukocyte adhesion.