Soluble L-selectin at levels present in septic patients diminishes leukocyte-endothelial cell interactions in mice in vivo:: A mechanism for decreased leukocyte delivery to remote sites in sepsis

Objective: Recent in vivo studies of both septic humans and animals demonstrate that leukocyte delivery is attenuated to sites remote from the primary infection. The mechanisms for this are not entirely clear. L-selectin is integral to rolling, the first step in leukocyte recruitment to an inflammatory site. L-setectin is shed from leukocytes in sepsis, resulting in increased levels of soluble L-selectin in plasma (2.33 mug/ml). This study investigates the effects of soluble L-selectin at levels found in sepsis on leukocyte trafficking in vivo. Design: Prospective, controlled trial. Setting: Surgical research laboratory in a university hospital. Subjects: Swiss white male mice of 25-35 g. Interventions: Mice were randomized to one of three study groups: soluble L-selectin 2.33, soluble L-selectin 8.0, or albumin. Intravital microscopy was performed on postcapillary venules of 20-40 mum in diameter in the cremaster muscle of mice. Leukocyte-endothelial cell interactions (rolling, adherence, and rolling velocity) were measured pre- and post- (1, 15, 30, and 45 mins) intravenous infusion of human recombinant soluble L-selectin (2.33 and 8.0 mug/mL) or human albumin (8.0 mug/mL). Measurements and Main Results:The intravenous administration of soluble L-selectin to a systemic concentration of 2.33 mug/mL diminished rolling significantly. Soluble L-selectin at 8.0 mug/mL decreased rolling and increased rolling velocity to a greater degree. Injection of albumin did not alter leukocyte-endothelial cell interactions at any time point. No difference between groups in blood pressure, shear rate, or leukocyte counts was detected. Conclusions: Soluble L-selectin diminishes leukocyte rolling at levels present in sepsis (2.33 mug/ml). This effect is dose dependent, and could not be explained by differences in blood pressure, shear rate, or leukocyte counts. These findings identify increased soluble L-selectin levels as one of the mechanisms for decreased leukocyte delivery and exudation to remote sites in septic patients.