Altered Kupffer cell function in biliary obstruction.
BACKGROUND
An altered Kupffer cell (KC) response is thought to be responsible for the characteristic phenotype observed after biliary obstruction: a phenotype marked by a defect in the hepatic reticuloendothelial system and a hypersensitivity to endotoxin. Few studies, however, have directly examined KC function. We have sought to define the specific alterations in function and phenotype that occur in the KC after biliary obstruction.


METHODS
KCs were isolated from female C57BL/6 mice 4 days after a sham or common bile duct ligation (CBDL) operation. Phagocytosis, oxidative burst potential, and intracellular bacterial killing were measured as markers of reticuloendothelial system function. The KC response to endotoxin was assessed by measuring tumor necrosis factor alpha and interleukin 6 levels in the media after stimulation with lipopolysaccharide (LPS) or with LPS plus LPS-binding protein (LBP).


RESULTS
CBDL KCs demonstrated a significant increase in phagocytic ability and significantly decreased baseline oxidative stress, compared with Shams. The oxidative burst potential, however, was equivalent or higher for CBDL KCs. CBDL KCs also demonstrated increased numbers of viable intracellular bacteria after infection; however, it is unclear if this finding represents impaired intracellular bacterial killing or increased phagocytosis of bacteria. With respect to the KC response to endotoxin, CBDL KCs were found to be less sensitive to the stimulatory effects of LPS alone but were exquisitely sensitive to the effects of LBP. LBP levels were found to be significantly elevated in CBDL animals, and CBDL KCs demonstrated a dose-dependent, exaggerated tumor necrosis factor alpha and interleukin 6 response to LPS administered with LBP.


CONCLUSIONS
KC function is clearly altered after biliary obstruction. Phagocytic ability is actually increased, although the ability of CBDL KCs to kill bacteria within the phagosome remains ill defined. CBDL KCs are exquisitely sensitive to the effects of LBP, and LBP levels are elevated after biliary obstruction. LBP may be responsible for the increased proinflammatory response observed after endotoxin challenge in animals with biliary obstruction.
Minter
Rebecca M
RM
Veterans Administration Ann Arbor Healthcare Systems, Department of Surgery, University of Michigan Medical School, 48109-0331, USA. rminter@umich.edu
Fan
Ming-Hui
MH
Sun
Jianmin
J
Niederbichler
Andreas
A
Ipaktchi
Kyros
K
Arbabi
Saman
S
Hemmila
Mark R
MR
Remick
Daniel G
DG
Wang
Stewart C
SC
Su
Grace L
GL
D000209:Acute-Phase Proteins / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology; D002478:Cells, Cultured; D002779:Cholestasis / Q000503:physiopathology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000502:physiology*; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D000099231:Lipopolysaccharide-Binding Protein