Assessment of the mechanism of juxtacrine activation and adhesion of leukocytes in liver microcirculation.

Leukotriene C4 (LTC4), histamine, and other mediators can induce expression of P-selectin and platelet-activating factor (PAF) on venular endothelium to recruit leukocytes in vivo and in vitro via a juxtacrine mechanism of adhesion. The objective of this study was to assess the effect of histamine and LTC4 on the leukocyte recruitment in the liver and to study the components and molecular mechanisms involved in this process. We visualized the hepatic microvasculature using intravital microscopy and we determined that LTC4 (20 nM) but not histamine (0.1, 0.3, or 1 mM) induced leukocyte recruitment in the liver microcirculation. Histamine could induce leukocyte recruitment but only in the presence of an antihistaminase. The LTC4-induced leukocyte recruitment occurred primarily in sinusoids (not venules) and was not inhibitable by three different anti-P-selectin antibodies (5H1, RMP-1, and RB40). Leukocyte recruitment in P-selectin-deficient mice, intercellular adhesion molecule 1 (ICAM-1)-deficient mice, and mice treated with a PAF antagonist was of the same magnitude as in wild-type animals in response to LTC4. Although PAF alone could induce adhesion in both sinusoids and postsinusoidal venules, this chemotactic agent was not involved in LTC4-induced adhesion in the liver. Finally, an overlapping role for P-selectin and ICAM-1 was ruled out as LTC4 induced leukocyte recruitment in P-selectin and ICAM-1 double-deficient mice. These data demonstrate that LTC4 does not activate the known early mechanisms of leukocyte recruitment, including P-selectin, PAF, or ICAM-1 in the hepatic microvasculature.