Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx

TY - JOUR

T1 - Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx

AU - Hempel, Casper

AU - Sporring, Jon

AU - Kurtzhals, Jørgen Anders Lindholm

PY - 2019

Y1 - 2019

N2 - Vascular pathology is central to malaria pathogenesis and associated with severity of disease.We have previously documented shedding of the cerebral endothelial glycocalyx in experimentalmalaria and hypothesized that this action is implicated in the pathogenesis of cerebralmalaria (CM).Quantification and characterization of the intraluminal vascular glycocalyx are technically challenging. Here, we used ferritin labeling, computerized image analysis, and biochemical characterization by using in vivo biotinylation and pull down. Image analysis divided micewithCMand uncomplicated malaria and uninfected control mice into 3 non-overlapping groups. Biochemical assessment of the luminal surface revealedmalaria-induced alterations in all components of the glycocalyx in CM. This loss wasmirrored in increases of the same components in peripheral blood samples. Corticosteroid treatment protected against CM, reduced inflammation, and prevented glycocalyx loss. Adjunctive antithrombin-3 also prevented glycocalyx loss and significantly reduced CM-associated mortality, as well as reduced local inflammation and prevented blood-brain barrier leakage. In contrast, inhibition of matrix metalloproteases with batimastat had limited effects on the glycocalyx and disease progression. Thus, glycocalyx loss may be associated with malaria pathogenesis and could be targeted by adjunctive treatment.

AB - Vascular pathology is central to malaria pathogenesis and associated with severity of disease.We have previously documented shedding of the cerebral endothelial glycocalyx in experimentalmalaria and hypothesized that this action is implicated in the pathogenesis of cerebralmalaria (CM).Quantification and characterization of the intraluminal vascular glycocalyx are technically challenging. Here, we used ferritin labeling, computerized image analysis, and biochemical characterization by using in vivo biotinylation and pull down. Image analysis divided micewithCMand uncomplicated malaria and uninfected control mice into 3 non-overlapping groups. Biochemical assessment of the luminal surface revealedmalaria-induced alterations in all components of the glycocalyx in CM. This loss wasmirrored in increases of the same components in peripheral blood samples. Corticosteroid treatment protected against CM, reduced inflammation, and prevented glycocalyx loss. Adjunctive antithrombin-3 also prevented glycocalyx loss and significantly reduced CM-associated mortality, as well as reduced local inflammation and prevented blood-brain barrier leakage. In contrast, inhibition of matrix metalloproteases with batimastat had limited effects on the glycocalyx and disease progression. Thus, glycocalyx loss may be associated with malaria pathogenesis and could be targeted by adjunctive treatment.

U2 - 10.1096/fj.201800657R

DO - 10.1096/fj.201800657R

M3 - Journal article

C2 - 30226810

SN - 0892-6638

VL - 33

SP - 2058

EP - 2071

JO - F A S E B Journal

JF - F A S E B Journal

IS - 2

ER -