Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine.

Abstract

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e., intramuscular penetration, have been described recently in various animal models, the preceding mechanism underlying the clinical manifestations of systemic ricin poisoning has not been completely defined. Here, we show that following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages. Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs. Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage. Finally, by using side-stream dark field intravital microscopy imaging, we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels. These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning, may serve for the formulation of specifically tailored therapies for treating parenteral ricin intoxication.

• Authors: Anita Sapoznikov, Yoav Gal, Yentl Evgy, Moshe Aftalion, Shahaf Katalan, Tamar Sabo, Chanoch Kronman, Reut Falach
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 22 (Nov 16 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34830227 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• Cadherins
• Sdc1 protein, mouse
• Syndecan-1
• Vascular Endothelial Growth Factor A
• cadherin 5
• vascular endothelial growth factor A, mouse
• Hyaluronic Acid
• Ricin
• Heparitin Sulfate

Topics

• Animals
• Antigens, CD (genetics, metabolism)
• Cadherins (genetics, metabolism)
• Dose-Response Relationship, Drug
• Endothelial Cells (cytology, drug effects, metabolism)
• Female
• Gene Expression (drug effects)
• Glycocalyx (chemistry, drug effects, metabolism)
• Heparitin Sulfate (chemistry, metabolism)
• Humans
• Hyaluronic Acid (chemistry, metabolism)
• Hydrolysis
• Injections, Intramuscular
• Kidney (drug effects, metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Mice
• Microcirculation (drug effects)
• Ricin (isolation & purification, toxicity)
• Ricinus (chemistry)
• Spleen (drug effects, metabolism, pathology)
• Swine
• Syndecan-1 (chemistry, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)