Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury.
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.
Zhai
Yuan
Y
Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, Los Angeles, CA 90095, USA.
Qiao
Bo
B
Shen
Xiu-Da
XD
Gao
Feng
F
Busuttil
Ronald W
RW
Cheng
Genhong
G
Platt
Jeffrey L
JL
Volk
Hans-Dieter
HD
Kupiec-Weglinski
Jerzy W
JW
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*
D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4