TNF-α induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin

Abstract

Background

Healthy vascular endothelium is clothed by the endothelial glycocalyx. This structure plays a key role in the regulation of inflammation and vascular permeability and is known to be degraded by ischemic and inflammatory stress. Our aim was to show whether hydrocortisone and antithrombin stabilize the glycocalyx and, therefore, the vascular barrier, against damage induced by the inflammatory stimulus TNF-α, thus improving the cardio-vascular situation.

Methods

Isolated guinea pig hearts were perfused with Krebs–Henseleit buffer for 20 min at constant flow (baseline perfusion pressure 70 cmH2O). Hydrocortisone in a stress dose (10 µg/ml) or antithrombin in a physiological dose (1 U/ml) were then applied for 15 min before infusion of TNF-α (4 ng/ml, 10 min). Coronary net fluid filtration was assessed directly by measuring transudate formation on the epicardial surface. Hearts were perfusion-fixed to visualize the glycocalyx.

Results

TNF-α induced severe degradation of the glycocalyx, increased coronary resistance, heightened vascular leak and permeability to hydroxyethyl starch and caused mast-cell degranulation. Hydrocortisone and antithrombin both reduced all of these effects. Electron microscopy revealed a mostly intact glycocalyx after treatment with either drug.

Conclusions

Both hydrocortisone and antithrombin clearly preserve the endothelial glycocalyx in the face of inflammatory degradation initiated by TNF-α, however, with different mechanisms. This is an important new facet in the pathophysiology and therapy of sepsis, since preservation of the glycocalyx should help prevent vasoconstriction, tissue edema as well as leukocyte and platelet adhesion, thus mitigating inflammation and tissue hypoxia.

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Acknowledgments

The study was performed using departmental resources and a competitive grant of the Friedrich Baur Foundation (0027/2007) of the Ludwig-Maximilians University, Munich, Germany.

Conflict of interest None of the authors have any conflicts of interest in connection with this work.

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Correspondence to Daniel Chappell MD.

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Returned for 1. Revision: 19 June 2008 1. Revision received: 12 August 2008 Returned for 2. Revision: 20 August 2008 2. Revision received: 21 August 2008

The work was performed at the Walter-Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Nussbaumstraße 20, 80336 Munich, Germany.

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Chappell, D., Hofmann-Kiefer, K., Jacob, M. et al. TNF-α induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol 104, 78 (2009). https://doi.org/10.1007/s00395-008-0749-5

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Keywords

  • TNF-α
  • glycocalyx
  • endothelium
  • hydrocortisone
  • antithrombin