Leukocyte-independent plasma extravasation during endotoxemia

Objectives: To determine the meaning of leukocyte-endothelial interactions for the development of endotoxin-induced vascular leakage. Design: Randomized, blinded, controlled trial. Setting: Experimental laboratory. Subjects: Twenty-four male Wistar rats. Interventions: After application of fucoidin to prevent leukocyte rolling a nd adherence (25 mg/kg: n = 8; fucoidin/LPS group) or saline 0.9% (n = 8; L PS group), animals were given an intravenous infusion of endotoxin (Escheri chia coli lipopolysaccharide O26:B6; 2 mg/kg/hr) over 120 mins. Animals in the control group (n = 8) received an equivalent volume of saline 0.9%. Measurements and Main Results: Leukocyte rolling and leukocyte adherence, r ed cell velocity, vessel diameters, venular wall shear rate, volumetric blo od flow, and macromolecular leakage were determined in mesenteric postcapil lary venules using in vivo videomicroscopy at baseline, 60 mins, and 120 mi ns after start of a continuous endotoxin infusion. Fucoidin prevented leuko cyte rolling (baseline, 3 +/- 2 rollers; 120 mins, 3 +/- 1 rollers; not sig nificant vs. baseline; p < .01 vs. LPS group) and reduced the adherence of leukocytes at baseline and during endotoxemia and showed only a slight incr ease in adherent leukocytes (baseline, 100 +/- 38 cells/mm(2); 120 mins, 24 4 +/- 68 cells/mm(2); p < .05 vs. baseline; p < .01 vs. LPS group). In the LPS group, endotoxin exposure induced a marked increase in adherent leukocy tes (baseline, 248 +/- 24 cells/mm(2); 120 mins, 560 +/- 57 cells/mm2; p < .01). Leukocyte adherence in control animals (control group) did not increa se significantly. Macromolecular leakage, expressed as the ratio of periven ular to intravenular fluorescence intensity after injection of fluorescence -labeled albumin, increased from 0.16 +/- 0.03 to 0.49 +/- 0.04 (p < .01 vs . baseline; p < .05 vs. control) during the infusion of endotoxin in the LP S group. Fucoidin application did not diminish the extravasation of albumin (baseline, 0.09 +/- 0.03; 120 mins, 0.61 +/- 0.10; p < .01 vs. baseline; p < .01 vs, control). Conclusions: These results demonstrate that despite a significant reduction of adherent leukocytes to the endothelium by fucoidin, there is no reducti on in macromolecular leakage, indicating that leukocyte-endothelial interac tions only play a minor role for the development of macromolecular leakage and microvascular damage in the early phase of endotoxemia.