p38 mitogen-activated protein kinase-dependent chemokine production, leukocyte recruitment, and hepatocellular apoptosis in endotoxemic liver injury.
OBJECTIVE
To determine the role of p38 mitogen-activated protein kinase (MAPK) signaling in endotoxin-induced liver injury.


BACKGROUND
MAPKs have been reported to play a potential role in regulating inflammatory responses, but the role of p38 MAPK signaling in chemokine production, leukocyte recruitment, and hepatocellular apoptosis in the liver of endotoxemic mice is not known.


METHODS
Endotoxin-induced leukocyte-endothelium interactions were studied by use of intravital fluorescence microscopy in the mouse liver. Tumor necrosis factor-alpha (TNF-alpha) and CXC chemokines, liver enzymes, and apoptosis were determined 6 hours after endotoxin challenge. The specific p38 MAPK inhibitor SB 239063 was given immediately prior to endotoxin exposure. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot.


RESULTS
Endotoxin increased phosphorylation and activity of p38 MAPK in the liver, which was markedly inhibited by SB 239063. Inhibition of p38 MAPK signaling dose-dependently decreased endotoxin-induced leukocyte rolling, adhesion, and sinusoidal sequestration of leukocytes. SB 239063 markedly reduced endotoxin-induced formation of TNF-alpha and CXC chemokines in the liver. Indeed, the endotoxin-provoked increase of liver enzymes and hepatocellular apoptosis were abolished and sinusoidal perfusion was restored in endotoxemic mice treated with SB 239063.


CONCLUSIONS
This study demonstrates that p38 MAPK signaling plays an important role in regulating TNF-alpha and CXC chemokine production in endotoxemic liver injury and that inhibition of p38 MAPK activity abolishes endotoxin-induced leukocyte infiltration as well as hepatocellular apoptosis. These novel findings suggest that interference with the p38 MAPK pathway may constitute a therapeutic strategy against septic liver damage.
Klintman
Daniel
D
Department of Surgery, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
Li
Xiang
X
Santen
Stefan
S
Schramm
Rene
R
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D019743:Chemokines, CXC / Q000096:biosynthesis*; D019446:Endotoxemia / Q000276:immunology / Q000473:pathology*; D036904:Leukocyte Rolling / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000293:injuries* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D015427:Reperfusion Injury; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases