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Therapeutic Restoration of Endothelial Glycocalyx in Sepsis

Authors
 J.W. Song  ;  J.A. Zullo  ;  D. Liveris  ;  M. Dragovich  ;  X.F. Zhang  ;  M.S. Goligorsky 
Citation
 Journal of Pharmacology and Experimental Therapeutics, Vol.361 : 115-121, 2017 
Journal Title
 Journal of Pharmacology and Experimental Therapeutics 
ISSN
 0022-3565 
Issue Date
2017
MeSH
Animals ; Anticoagulants/pharmacology ; Anticoagulants/therapeutic use ; Capillary Permeability/drug effects ; Capillary Permeability/physiology ; Cells, Cultured ; Endothelial Cells/drug effects* ; Endothelial Cells/pathology ; Endothelial Cells/physiology* ; Glycocalyx/drug effects* ; Glycocalyx/pathology ; Glycocalyx/physiology* ; Glycosaminoglycans/pharmacology ; Glycosaminoglycans/therapeutic use* ; Male ; Mice ; Mice, Inbred C57BL ; Sepsis/drug therapy* ; Sepsis/pathology ; Sepsis/physiopathology
Abstract
Endothelial glycocalyx (EG) is disintegrated during sepsis. We have previously shown that this occurs very early in the course of sepsis and its prevention improves the survival of mice with sepsis. Here, we sought to investigate the possibility of pharmacologically accelerating the restoration of disintegrated EG in sepsis. We used a soilage injection model to induce polymicrobial sepsis in C57/BL6 mice and measured total body EG. En face aortic preparations were used for staining of markers of EG and atomic force microscopy was used to measure EG in vitro. In vitro studies were conducted in cultured endothelial cells either exposed to a lipopolysaccharide or enzymatically denuded of EG. Sulodexide (SDX), a heparin sulfate-like compound resistant to degradation by heparanase, accelerated EG regeneration in vitro and in vivo. The total volume of EG was drastically reduced in septic mice. Administration of SDX produced a dramatic acceleration of EG restoration. This effect, unrelated to any SDX-induced differences in microbial burden, was associated with better control of vascular permeability. Notably, SDX demonstrated not only a remarkable capacity for EG regeneration in vitro and in vivo but was also associated with improved animal survival, even when instituted 2 hours after induction of severe sepsis. In conclusion, 1) EG is disintegrated in sepsis, the event which contributes to high animal mortality; 2) pharmacologic acceleration of EG restoration can be achieved using SDX; and 3) SDX reduces vascular permeability, which is elevated in septic mice, and improves animal survival.
Full Text
http://jpet.aspetjournals.org/content/361/1/115.long
DOI
10.1124/jpet.116.239509
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
송종욱(Song, Jong Wook) ORCID logo https://orcid.org/0000-0001-7518-2070
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154465
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