title: 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).
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Trauma Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Korff
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.forename: Chanchun
authors.initials: C
authors.lastname: Cai
authors.forename: Yi Shan
authors.initials: YS
authors.lastname: Lee
authors.forename: Melanie
authors.initials: M
authors.lastname: Scott
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D004187:Disaccharides / Q000627:therapeutic use*; D005264:Femoral Fractures / Q000150:complications / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013403:Sugar Phosphates / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism; D014947:Wounds and Injuries / Q000150:complications* / Q000378:metabolism
chemical_list: D004187:Disaccharides; D015850:Interleukin-6; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D013403:Sugar Phosphates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C512420:eritoran; D000637:Transaminases
keywords: DAMPs; Liver; Mice; Organ damage; Tight junctions; Toll-like receptor