title: CD14 contributes to warm hepatic ischemia-reperfusion injury in mice.
abstract: BACKGROUND
  Ischemia/reperfusion (I/R) of the liver contributes to the pathobiology of liver injury in transplantation, liver surgery, and hemorrhagic shock. Ischemia/reperfusion induces an inflammatory response that is driven, in part, by Toll-like receptor 4 (TLR) signaling. CD14 is known to participate in the function of TLR4. We hypothesized that CD14 would be involved in the pathobiology of warm hepatic I/R.
  
  
  METHODS
  Using a 70% liver inflow inclusion model, CD14 knockout and wild-type (WT) mice were subjected to 1-h warm ischemia followed by reperfusion. CD14 mRNA, circulating transaminase, interleukin 6, soluble CD14, and high-mobility group box 1 (HMGB1) levels were measured. CD14 neutralizing antibody or isotype control antibody was given before ischemia or reperfusion for CD14 blockade in WT mice. Recombinant HMGB1 was given before reperfusion in some experiments to test if liver injury worsens.
  
  
  RESULTS
  There was an upregulation of CD14 mRNA in reperfused livers together with increased soluble CD14 levels in the circulation. Compared with WT control mice, CD14 knockout mice had much lower alanine aminotransferase and interleukin 6 levels at 6 and 24 h following I/R, and much less liver necrosis by histology. TUNEL (terminal deoxynucleotidyl-transferase dUTP nick end labeling) staining displayed less apoptosis at 24 h in the absence of CD14. CD14 blockage by neutralizing antibody also attenuated liver injury and the inflammatory response in C57BL/6 mice following I/R, but did not provide additional protection to TLR4 mutant C3H/Hej mice. CD14 deficiency did not change circulating HMGB1 levels following I/R (6 h). A dose of recombinant HMGB1, which worsened hepatic injury when given before reperfusion in WT mice, did not increase liver damage in CD14-deficient mice.
  
  
  CONCLUSIONS
  CD14 is actively involved in hepatic I/R injury. Its deficiency or blockade ischemia attenuates liver injury and inflammatory response. CD14 mediates liver damage and inflammatory responses in the setting of warm hepatic I/R in mice.
authors: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors: Changchun
authors: C
authors: Cai
authors: Xiaolian
authors: X
authors: Shi
authors: Sebastian
authors: S
authors: Korff
authors: Jinxiang
authors: J
authors: Zhang
authors: Patricia A
authors: PA
authors: Loughran
authors: Xiangcai
authors: X
authors: Ruan
authors: Yong
authors: Y
authors: Zhang
authors: Li
authors: L
authors: Liu
authors: Timothy R
authors: TR
authors: Billiar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000097:blood; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024243:HMGB1 Protein; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors
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