Eritoran attenuates tissue damage and inflammation in hemorrhagic shock/trauma.

Abstract

BACKGROUND:

Severe injury and associated hemorrhagic shock lead to an inflammatory response and subsequent increased tissue damage. Numerous reports have shown that injury-induced inflammation and the associated end-organ damage is driven by Toll-like receptor 4 (TLR4) activation via damage-associated molecular patterns. We examined the effectiveness of Eritoran tetrasodium (E5564), an inhibitor of TLR4 function, in reducing inflammation induced during hemorrhagic shock with resuscitation (HS/R) or after peripheral tissue injury (bilateral femur fracture, BFF).

MATERIAL AND METHODS:

Mice underwent HS/R or BFF with or without injection of Eritoran (5 mg/kg body weight) or vehicle control given before, both before and after, or only after HS/R or BFF. Mice were sacrificed after 6 h and plasma and tissue cytokines, liver damage (histology; aspartate aminotransferase/alanine aminotransferase), and inflammation (NF-κB) and gut permeability were assessed.

RESULTS:

In HS/R Eritoran significantly reduced liver damage (values ± SEM: alanine aminotransferase 9910 ± 3680 U/L versus 1239 ± 327 U/L and aspartate aminotransferase 5863 ± 2000 U/L versus 1246 ± 243 U/L, P < 0.01) at 6 h compared with control when given just before HS and again just prior to resuscitation. Eritoran administration also led to lower IL-6 levels in plasma and liver and less NF-κB activation in liver. Increases in gut barrier permeability induced by HS/R were also prevented with Eritoran. Eritoran similarly diminished BFF-mediated systemic inflammatory responses.

CONCLUSION:

These data suggest Eritoran can inhibit tissue damage and inflammation induced via TLR4/myeloid differentiation factor 2 signaling from damage-associated molecular patterns released during HS/R or BFF. Eritoran may represent a promising therapeutic for trauma patients to prevent multiple organ failure.

• Authors: Sebastian Korff, Patricia Loughran, Chanchun Cai, Yi Shan Lee, Melanie Scott, Timothy R Billiar
• Journal: The Journal of surgical research (J Surg Res) Vol. 184 Issue 2 Pg. e17-25 (Oct 2013) ISSN: 1095-8673 [Electronic] United States
• PMID: 23777984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Disaccharides
• Interleukin-6
• Ly96 protein, mouse
• Lymphocyte Antigen 96
• NF-kappa B
• Sugar Phosphates
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• eritoran
• Transaminases

Topics

• Animals
• Disaccharides (therapeutic use)
• Femoral Fractures (complications, metabolism)
• Inflammation (metabolism, prevention & control)
• Interleukin-6 (metabolism)
• Lymphocyte Antigen 96 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Animal
• NF-kappa B (metabolism)
• Shock, Hemorrhagic (complications, metabolism)
• Signal Transduction (physiology)
• Sugar Phosphates (therapeutic use)
• Toll-Like Receptor 4 (antagonists & inhibitors, metabolism)
• Transaminases (metabolism)
• Wounds and Injuries (complications, metabolism)