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(Circulation Research. 1995;77:879.)
© 1995 American Heart Association, Inc.

Articles

Leukotriene C₄/D₄ Induces P-Selectin and Sialyl Lewis^x–Dependent Alterations in Leukocyte Kinetics In Vivo

Samina Kanwar, Brent Johnston, Paul Kubes

From the Immunology Research Group, University of Calgary (Canada).

Correspondence to Dr Paul Kubes, Department of Medical Physiology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

Abstract The objective of this study was to assess the effect of leukotriene C₄ (LTC₄) on the flux of rolling leukocytes, leukocyte rolling velocity, and leukocyte adhesion in postcapillary venules in vivo and to study the underlying molecular mechanisms involved. LTC₄ (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). LTC₄ also induced a significant reduction in leukocyte rolling velocity, an event that was independent of P-selectin but entirely dependent on sLe^x. This LTC₄-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 >5000 times the concentration of LTC₄. Treatment with an anti–L-selectin antibody had no effect on the LTC₄-induced increase in leukocyte rolling or reduction in rolling velocity. Inhibition of LTC₄ bioconversion to LTD₄ by pretreatment with L-serine (100 µmol/L) prevented the LTC₄-induced increase in leukocyte rolling flux and the LTC₄-induced reduction in leukocyte rolling velocity. A subtle, yet significant, increase in leukocyte adhesion was also observed with LTC₄. Pretreatment with a platelet-activating factor receptor antagonist returned the LTC₄-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 LTC₄ but not histamine. This study demonstrates that LTC₄, via bioconversion to leukotriene D₄, 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.

Key Words: leukotriene C₄ • leukocyte rolling • sialyl Lewis^x • P-selectin

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