The mechanisms and physiological relevance of glycocalyx degradation in hepatic ischemia/reperfusion injury

TY - JOUR

T1 - The mechanisms and physiological relevance of glycocalyx degradation in hepatic ischemia/reperfusion injury

AU - van Golen, Rowan F

AU - Reiniers, Megan J

AU - Vrisekoop, Nienke

AU - Zuurbier, Coert J

AU - Olthof, Pim B

AU - van Rheenen, Jacco

AU - van Gulik, Thomas M

AU - Parsons, Barry J

AU - Heger, Michal

PY - 2014/9/1

Y1 - 2014/9/1

N2 - SIGNIFICANCE: Hepatic ischemia/reperfusion (I/R) injury is an inevitable side effect of major liver surgery that can culminate in liver failure. The bulk of I/R-induced liver injury results from an overproduction of reactive oxygen and nitrogen species (ROS/RNS), which inflict both parenchymal and microcirculatory damage. A structure that is particularly prone to oxidative attack and modification is the glycocalyx (GCX), a meshwork of proteoglycans and glycosaminoglycans (GAGs) that covers the lumenal endothelial surface and safeguards microvascular homeostasis. ROS/RNS-mediated degradation of the GCX may exacerbate I/R injury by, for example, inducing vasoconstriction, facilitating leukocyte adherence, and directly activating innate immune cells.RECENT ADVANCES: Preliminary experiments revealed that hepatic sinusoids contain a functional GCX that is damaged during murine hepatic I/R and major liver surgery in patients. There are three ROS that mediate GCX degradation: hydroxyl radicals, carbonate radical anions, and hypochlorous acid (HOCl). HOCl converts GAGs in the GCX to GAG chloramides that become site-specific targets for oxidizing and reducing species and are more efficiently fragmented than the parent molecules. In addition to ROS/RNS, the GAG-degrading enzyme heparanase acts at the endothelial surface to shed the GCX.CRITICAL ISSUES: The GCX seems to be degraded during major liver surgery, but the underlying cause remains ill-defined.FUTURE DIRECTIONS: The relative contribution of the different ROS and RNS intermediates to GCX degradation in vivo, the immunogenic potential of the shed GCX fragments, and the role of heparanase in liver I/R injury all warrant further investigation.

AB - SIGNIFICANCE: Hepatic ischemia/reperfusion (I/R) injury is an inevitable side effect of major liver surgery that can culminate in liver failure. The bulk of I/R-induced liver injury results from an overproduction of reactive oxygen and nitrogen species (ROS/RNS), which inflict both parenchymal and microcirculatory damage. A structure that is particularly prone to oxidative attack and modification is the glycocalyx (GCX), a meshwork of proteoglycans and glycosaminoglycans (GAGs) that covers the lumenal endothelial surface and safeguards microvascular homeostasis. ROS/RNS-mediated degradation of the GCX may exacerbate I/R injury by, for example, inducing vasoconstriction, facilitating leukocyte adherence, and directly activating innate immune cells.RECENT ADVANCES: Preliminary experiments revealed that hepatic sinusoids contain a functional GCX that is damaged during murine hepatic I/R and major liver surgery in patients. There are three ROS that mediate GCX degradation: hydroxyl radicals, carbonate radical anions, and hypochlorous acid (HOCl). HOCl converts GAGs in the GCX to GAG chloramides that become site-specific targets for oxidizing and reducing species and are more efficiently fragmented than the parent molecules. In addition to ROS/RNS, the GAG-degrading enzyme heparanase acts at the endothelial surface to shed the GCX.CRITICAL ISSUES: The GCX seems to be degraded during major liver surgery, but the underlying cause remains ill-defined.FUTURE DIRECTIONS: The relative contribution of the different ROS and RNS intermediates to GCX degradation in vivo, the immunogenic potential of the shed GCX fragments, and the role of heparanase in liver I/R injury all warrant further investigation.

U2 - 10.1089/ars.2013.5751

DO - 10.1089/ars.2013.5751

M3 - Article

C2 - 24313895

SN - 1523-0864

VL - 21

SP - 1098

EP - 1118

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

IS - 7

ER -