Abstract
ABSTRACTHepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation.
Highlights
Hepatic failure is an important risk factor for poor outcome in septic patients
Previously, we characterized vascular glycocalyx (VGC) remodeling after S. aureus challenge to ascertain its composition during severe hepatic damage and pathology [13], but these studies were performed at 24 h postinfection
To characterize VGC remodeling during the initial stages of liver inflammation [18], we applied a similar chemical tagging and proteomics workflow to a murine model of S. aureus sepsis 6 h postinfection
Summary
Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury. Remodeling of the VGC during sepsis is partially driven by upregulation of endogenous glycosidases and proteases, resulting in shedding of glycan fragments and protein ectodomains that can fuel dysregulated inflammatory loops by acting as damage-associated molecular patterns (DAMPs) [9, 14, 15]
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