Endothelial Glycocalyx Damage During Endotoxemia Coincides With Microcirculatory Dysfunction and Vascular Oxidative Stress

Abstract

The glycocalyx constitutes the first line of the blood tissue interface and is thus involved in many physiological processes, deregulation of which may lead to microvascular dysfunction. Because administration of LPS is accompanied by severe microvascular dysfunction, the purpose of the study was to investigate microvascular glycocalyx function during endotoxemia. Bolus infusion of LPS (10 mg kg(-1)) to male Sprague-Dawley rats elicited the development of hyporeactivity to vasoactive agents and microvascular derangements, including decreased capillary density and significant increases in intermittent and stopped flow capillaries in the small intestine muscularis layer compared with controls. LPS elicited plasma hyluronan release and reduction in endothelial surface thickness, indicative of glycocalyx degradation. Because endothelial glycocalyx is extremely sensitive to free radicals, oxidative stress was evaluated by oxidation of dihydrorhodamine in microvascular beds and levels of heart malondialdehyde and plasma carbonyl proteins, which were all increased in LPS-treated rats. Activated protein C (240 microg kg(-1) h(-1)) enhanced systemic arterial pressure response to norepinephrine in LPS-treated rats. Activated protein C (240 microg kg(-1) h(-1)) prevented capillary perfusion deficit in the septic microvasculature that were associated with reduced oxidative stress and preservation of glycocalyx. Our findings support the conclusion that LPS induces major microcirculation dysfunction accompanied by microvascular oxidative stress and glycocalyx degradation that may be limited by activated protein C treatment.

Sepsis- The Dilemma Continues

“…There are alterations in the glycocalyx, the thin protein on the surface of the endothelial cell that contains antithrombin and superoxide dismutase. There is also a decrease in is size [25][26][27] and increase in its products of degradation in the blood [26,28]. This in turn leads to leukocyte rolling and adhesion to the surface of the endothelium as well as impairing the circulation of RBCs leading to impaired release of nitrous oxide (NO).…”

Microcirculatory assessment in daily clinical practice - not yet ready but not too far!

“…Interestingly, it seems that the anticoagulant properties of the drug may not be implicated in these microvascular effects. Improvement in white blood cell rolling and adhesion as well as preservation of glycocalyx may also be implicated (20,(52)(53) .…”

“…All animal studies assessing the effects of activated protein C on microcirculation reported a beneficial effect (20,(52)(53) . We showed evidence of a beneficial impact on perfused capillary proportion as early as four hours after the beginning of activated protein C infusion in septic patients with an on/off pattern (54) .…”

“…Furthermore, glycocalyx, a thin layer of glycolipids, glycoprotein, and proteoglycans that lines the luminal surface of endothelial cells, has major functions, such as control of vascular permeability, blood flow resistance, leukocyte adherence, and platelet activation. Recently, glycocalyx has gained great attention after some reports of glycocalyx disruption and endothelial dysfunction in sepsis and other inflammatory diseases (20,21) . Finally, and still controversial, mitochondrial dysfunction could be associated with signs of microcirculatory insufficiency, but whether it is a cause or a consequence of oxygen extraction deficit is still a matter of debate even though experimental data suggest that microvascular alteration precedes (and may lead to) mitochondrial dysfunction (22) .…”

“…Topical application of acetylcholine has been shown to totally reverse microvascular abnormalities in patients with sepsis (12,20) as well as in patients with severe heart failure (9) . One may thus ask whether systemic vasodilator agents also improve the microcirculation.…”