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.
Keywords
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Article info
Publication history
Published online: March 29, 2013
Accepted:
March 7,
2013
Received in revised form:
February 28,
2013
Received:
December 27,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
