Abstract
BackgroundActivation of the endothelium, complement activation and generation of cytokines are known events during ischemia-reperfusion (I/R) that mediate tissue injury. Our aim was to elucidate their respective participation at the onset of the reperfusion phase. Tourniquet application in hand surgery causes short-term ischemia, followed by reperfusion and was therefore used as the model in this study.MethodsTen patients were included in the study after obtaining informed consent. A tourniquet was placed on the upper arm and inflated to 250 mmHg for 116 ± 16 min, during which the surgery was performed. Venous blood and tissue samples from the surgical area were taken at baseline as well as 0, 2, and 10 min after reperfusion and analyzed for the following parameters: Endothelial integrity and/or activation were analyzed by measuring heparan sulfate and syndecan-1 in serum, and vWF, heparan sulfate proteoglycan as well as CD31on tissue. Complement activation was determined by C3a and C4d levels in plasma, levels of C1-inhibitor in serum, and IgG, IgM, C3b/c, and C4b/c deposition on tissue. Cytokines and growth factors IL-5, IL-6, IL-7, IL-8, IL-10, IL-17, G-CSF, GM-CSF, MCP-1, TNFα, VEGF, and PDGF bb were measured in the serum. Finally, CK-MM levels were determined in plasma as a measure for muscle necrosis.ResultsMarkers for endothelial activation and/or integrity as well as complement activation showed no significant changes until 10 min reperfusion. Among the measured cytokines, IL-6, IL-7, IL-17, TNFα, GM-CSF, VEGF, and PDGF bb were significantly increased at 10 min reperfusion with respect to baseline. CK-MM showed a rise from baseline at the onset of reperfusion (p < 0.001) and dropped again at 2 min (p < 0.01) reperfusion, suggesting ischemic muscle damage.ConclusionsIn this clinical model of I/R injury no damage to the endothelium, antibody deposition or complement activation were observed during early reperfusion. However, an increase of pro-inflammatory cytokines and growth factors was shown, suggesting a contribution of these molecules in the early stages of I/R injury.
Highlights
Activation of the endothelium, complement activation and generation of cytokines are known events during ischemia-reperfusion (I/R) that mediate tissue injury
Shedding of glycocalyx and endothelial cells (EC) integrity/activation Heparan sulfate and syndecan-1 were measured by ELISA
We measured the levels of shed heparan sulfate, syndecan-1 in serum and expression of heparan sulfate proteoglycan (HSPG) on tissue, which showed no changes from baseline to 10 min reperfusion
Summary
Activation of the endothelium, complement activation and generation of cytokines are known events during ischemia-reperfusion (I/R) that mediate tissue injury. The glycocalyx covering the endothelium, plays a critical role in maintaining the homeostasis of the blood vessel wall [1]. Glycocalyx shedding activates the endothelium by transforming it into a pro-inflammatory and pro-coagulant phenotype [4], thereby propagating injury. The glycocalyx acts as an interface between blood and tissue, forms receptors for many inflammatory molecules including cytokines and participates in inflammation [5,6]. Shedding of the glycocalyx after 2 min of reperfusion has been shown in humans [7], but the respective study was based on a setting of cardiopulmonary bypass and data on I/R induced shedding of the glycocalyx in smaller, peripheral blood vessels are lacking
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