P-selectin glycoprotein ligand-1 regulates chemokine-dependent leukocyte recruitment in colonic ischemia-reperfusion.

Objective and design: Leukocyte recruitment is a key feature in ischemia-reperfusion (I/R) -provoked tissue injury. This study evaluated the role of P-selectin-glycoprotein ligand-1 (PSGL-1) in CXC chemokine- and ischemia-reperfusion- induced leukocyte rolling and adhesion in the colon. Materials Balb/c mice were used in an inverted intravital fluorescence microscopy study of the microvascular bed in the colon. Treatment: Mice were challenged with macrophage inflammatory protein-2 (MIP-2) intraperitonally and leukocyte-endothelium interactions were analysed 3 h later. In separate experiments, mice were exposed to I/R by clamping of the superior mesenteric artery for 30 min and leukocyte rolling and adhesion were analysed after 120 min of reperfusion. Results: MIP-2 dose-dependently increased leukocyte rolling and adhesion in the colon. Pretreatment with an anti-PSGL-1 antibody reduced MIP-2-provoked leukocyte rolling and adhesion by more than 89%. I/R increased expression of MIP-2 as well as leukocyte rolling and adhesion. Immunoneutralization of PSGL-1 decreased reperfusion-induced leukocyte rolling by 85% and adhesion by 93% in colonic venules. Conclusions: Our data demonstrates that PSGL-1 is a dominant adhesion molecule supporting MIP-2- and I/R-provoked leukocyte rolling. Inhibition of PSGL-1 abolished leukocyte rolling and abrogated I/R-induced leukocyte adhesion in colonic venules. These findings suggest that targeting PSGL-1 may be an effective strategy to prevent I/R-induced inflammation in the colon