• Juan Zhou, Marieke Soltow, Katrin Zimmermann, Dragan Pavlovic, Brent Johnston, and Christian Lehmann.
• Department of Anesthesia, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada; Department of Microbiology & Immunology, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada.
• Microvasc. Res. 2015 Sep 1; 101: 33-7.

IntroductionToll like receptor 4 (TLR4) represents a critical cellular link for endotoxin-induced pathology. The aim of this study was to evaluate the potential role of TLR4 inhibition on the intestinal microcirculation during experimental endotoxemia.Materials And MethodsThe intestinal microcirculation was studied by intravital microscopy in four groups of Lewis rats (n=10 per group): healthy controls (CON group), endotoxemic animals (15mg/kg lipopolysaccharide, LPS group), endotoxemic animals treated with a TLR4 antagonist (1mg/kg CRX-526, LPS+CRX526 group), and controls treated with CRX-526 (C-CRX526 group). Plasma samples were obtained for cytokine measurements at the end of the experiments.ResultsEndotoxemia significantly increased leukocyte adhesion in intestinal submucosal venules (e.g., V1 venules: CON 20.4±6.5n/mm(2), LPS 237.5±36.2n/mm(2), p<0.05) and reduced capillary perfusion of the intestinal wall (e.g., longitudinal muscular layer: CON 112.5±5.9cm/cm(2), LPS 71.3±11.0cm/cm(2), p<0.05) at 2h. TLR4 inhibition significantly reduced endotoxemia-associated leukocyte adhesion (V1 venules: 104.3±7.8n/mm(2)) and improved capillary perfusion (longitudinal muscular layer: 111.0±12.3cm/cm(2)). Cytokine release was not significantly affected.ConclusionsThe TLR4 pathway may be a target in clinical Gram-negative sepsis since administration of the TLR4 antagonist CRX-526 improved intestinal microcirculation parameters in experimental endotoxemia.Copyright © 2015 Elsevier Inc. All rights reserved.

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