Tumor necrosis factor-alpha inhibition protects against endotoxin-induced endothelial glycocalyx perturbation

M. Nieuwdorp, M. C. Meuwese, H. L. Mooij, M. H. P. van Lieshout, A. Hayden, M. [=Marcel M.] Levi, J. C. M. Meijers, C. Ince, J. J. P. Kastelein, H. Vink, E. S. G. Stroes

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Abstract

Objective: inflammatory stimuli profoundly increase the Vulnerability of the vessel wall to atherogenesis. The endothelial glycocalyx, a layer of glycosaminoglycans and proteoglycans covering the luminal side of the vasculature, has recently emerged as an orchestrator of vascular homeostasis. In the present study, we investigated whether endotoxin-induced inflammatory reactions lead to a decrease of endothelial,glycocalyx thickness in humans and whether tumor necrosis factor-alpha (TNF alpha) plays a role in this process. Design. subjects and intervention: Healthy male Volunteers received low-dose endotoxin (1 ng/kg) intravenously, with (n = 8) or without (n = 13) pre-treatment with the soluble TNF alpha receptor etanercept. Endothelial glycocalyx thickness and related parameters were determined after endotoxin challenge. Results: Endotoxin resulted in a profound reduction in microvascular glycocalyx thickness (from 0.60 +/- 0.1 to 0.30 +/- 0.1 mu m, p <0.01). Concomitantly, plasma levels of the principal glycocalyx Constituent hyaluronan (62 +/- 18 to 85 +/- 24 ng/mL, p <0.05), monocyte activation and coagulation activation increased (F1 + 2; 0.3 +/- 0.1 to 2.8 +/- 1.5 nmol/L, p <0.05 and D-dimer; from 0.2 +/- 0.1 to 0.4 +/- 0.1 mg/L, p <0.05 compared to baseline). Inhibition of TNF alpha by etanercept attenuated loss of microvascular glycocalyx thickness (0.54 +/- 0.1 to 0.35 +/- 0.1 mu m. p <0.05). Changes in hyaluronan (58 +/- 13 to 46 +/- 10 ng/mL, p <0.05) and coagulation activation were also attenuated (F1 + 2; 0.3 +/- 0.1 to 2.1 +/- 0.9 nmol/L and D-dimer from 0.2 +/- 0.1 to 0.3 +/- 0.1 mg/L, p <0.05 compared to baseline). Conclusions: These data suggest that inflammatory activity, in part mediated by TNF alpha, leads to perturbation of the endothelial glycocalyx in humans. This may contribute to the vascular Vulnerability induced by inflammation. (C) 2008 Elsevier Ireland Ltd. All rights reserved
Original languageEnglish
Pages (from-to)296-303
JournalAtherosclerosis
Volume202
Issue number1
DOIs
Publication statusPublished - 2009

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