Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis.

Abstract

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

• Authors: Toshiaki Iba, Jerrold H Levy, Koichiro Aihara, Katsuhiko Kadota, Hiroshi Tanaka, Koichi Sato, Isao Nagaoka
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 1 (Dec 26 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33375342 (Publication Type: Journal Article)

Chemical References

• Antithrombins
• Endotoxins
• Protective Agents
• Recombinant Proteins
• Antithrombin III

Topics

• Animals
• Antithrombin III (pharmacology)
• Antithrombins (pharmacology)
• Endothelium, Vascular (drug effects, metabolism)
• Endotoxins (toxicity)
• Glycocalyx (drug effects, metabolism)
• Protective Agents (pharmacology)
• Rats
• Rats, Wistar
• Recombinant Proteins (administration & dosage)
• Sepsis (chemically induced, drug therapy, pathology)