TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin.
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-alpha, 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 cmH(2)O). Hydrocortisone in a stress dose (10 microg/ml) or antithrombin in a physiological dose (1 U/ml) were then applied for 15 min before infusion of TNF-alpha (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-alpha 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-alpha, 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.
Chappell
Daniel
D
Clinic of Anaesthesiology, Ludwig-Maximilians University, Nussbaumstrasse 20, Munich, Germany. daniel.chappell@med.uni-muenchen.de
Hofmann-Kiefer
Klaus
K
Jacob
Matthias
M
Rehm
Markus
M
Briegel
Josef
J
Welsch
Ulrich
U
Conzen
Peter
P
Becker
Bernhard F
BF
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005122:Exudates and Transudates / Q000502:physiology; D019276:Glycocalyx / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000032:analysis; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D006895:Hydroxyethyl Starch Derivatives / Q000032:analysis; D007511:Ischemia / Q000503:physiopathology; D007773:Lactates / Q000032:analysis; D011687:Purines / Q000032:analysis; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014527:Uric Acid / Q000032:analysis
D000991:Antithrombins; D006895:Hydroxyethyl Starch Derivatives; D007773:Lactates; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid; D006632:Histamine; D006854:Hydrocortisone