title: Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury.
abstract: BACKGROUND
  Although toll-like receptor 4 (TLR4) activation has been demonstrated to play a key role in the induction of intrahepatic inflammation, leading to hepatocellular damage in liver ischemia/reperfusion injury (IRI), the nature of TLR4 ligands generated during tissue injury remains to be elucidated. We hypothesized that endogenous TLR4 ligands, rather than endotoxin (lipopolysaccharide [LPS]), are instrumental in the activation of liver TLR4 leading to local inflammation response that culminates in ultimate organ IRI.
  
  
  RESULTS
  By using the LPS-neutralizing agent, recombinant bactericidal/permeability-increasing protein, we showed that the endotoxin blockade failed to protect mouse livers from warm IRI, as assessed by serum alanine aminotransferase levels, intrahepatic inflammatory gene induction profile, and liver pathology. The recombinant bactericidal/permeability-increasing protein did not cause any hepatocytoxicity by itself if injected into normal naive mice. Furthermore, we demonstrated that liver perfusates, generated by isolated liver perfusion system, contained LPS-independent, heat-sensitive protein molecules that activated macrophages to produce tumor necrosis factor (TNF)-alpha through TLR4 but not TLR2 pathway.
  
  
  CONCLUSIONS
  This study provides a definitive evidence that endogenous TLR4 ligands are critical in the pathogenesis of liver IRI.
authors.affiliation: Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, Los Angeles, CA 90095, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.forename: Bo
authors.initials: B
authors.lastname: Qiao
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Platt
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008102:Liver Circulation; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011169:Portal Vein / Q000503:physiopathology; D015427:Reperfusion Injury / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4