Abstract
Endothelial activation with excessive recruitment and adhesion of immune cells plays a central role in the progression of sepsis. We established a microfluidic system to study the activation of human umbilical vein endothelial cells by conditioned medium containing plasma from lipopolysaccharide-stimulated whole blood or from septic blood and to investigate the effect of adsorption of inflammatory mediators on endothelial activation. Treatment of stimulated whole blood with polystyrene-divinylbenzene-based cytokine adsorbents (average pore sizes 15 or 30 nm) prior to passage over the endothelial layer resulted in significantly reduced endothelial cytokine and chemokine release, plasminogen activator inhibitor-1 secretion, adhesion molecule expression, and in diminished monocyte adhesion. Plasma samples from sepsis patients differed substantially in their potential to induce endothelial activation and monocyte adhesion despite their almost identical interleukin-6 and tumor necrosis factor-alpha levels. Pre-incubation of the plasma samples with a polystyrene-divinylbenzene-based adsorbent (30 nm average pore size) reduced endothelial intercellular adhesion molecule-1 expression to baseline levels, resulting in significantly diminished monocyte adhesion. Our data support the potential of porous polystyrene-divinylbenzene-based adsorbents to reduce endothelial activation under septic conditions by depletion of a broad range of inflammatory mediators.Electronic supplementary materialThe online version of this article (doi:10.1007/s10753-016-0408-1) contains supplementary material, which is available to authorized users.
Highlights
As a barrier between the blood stream and the surrounding tissues, the endothelium orchestrates tissue homeostasis, angiogenesis, and hemostasis; contributes to innate immunity; and plays a major role in regulating the physiological as well as the pathological host response to infection [1, 2]
To study endothelial activation under septic conditions and to investigate the influence of mediator adsorption with polystyrene-divinylbenzene-based polymers on endothelial activation, we used a static model as well as a microfluidic approach based on human umbilical vein endothelial cells and primary human monocytes or monocytic THP-1 cells
Monocytes were chosen to study leukocyte adhesion, as they act as sentinels in the earliest stages of sepsis and guide neutrophils towards inflammatory foci [24, 25]
Summary
As a barrier between the blood stream and the surrounding tissues, the endothelium orchestrates tissue homeostasis, angiogenesis, and hemostasis; contributes to innate immunity; and plays a major role in regulating the physiological as well as the pathological host response to infection [1, 2]. The development of adjunctive sepsis therapies remains a major challenge due to the complex pathogenesis of this inflammatory syndrome and due to the vast heterogeneity of septic patients [5,6,7]. Extracorporeal therapies, such as high-volume hemofiltration, high cut-off hemodialysis, coupled plasma filtration adsorption, and, in particular, hemosorption have delivered promising pre-clinical and early clinical results, but have not yet been translated into clinical routine [8,9,10]. In addition to the depletion of soluble mediators, extracorporeal therapies have been proposed to act at the cellular level, modulating immune function by direct or indirect interaction with immune cells [11, 12]
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