Therapeutic Restoration of Endothelial Glycocalyx in Sepsis.
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.
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.) sjw72331@yuhs.ac.
J W
JW
Song
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.).
J A
JA
Zullo
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.).
D
D
Liveris
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.).
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M
Dragovich
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.).
X F
XF
Zhang
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.) sjw72331@yuhs.ac.
M S
MS
Goligorsky
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D019276:Glycocalyx / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D006025:Glycosaminoglycans / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D000925:Anticoagulants; D006025:Glycosaminoglycans; C007858:glucuronyl glucosamine glycan sulfate