Staphylococcal enterotoxin A-induced hepatotoxicity is predominantly mediated by Fas ligand (CD95L).
OBJECTIVE
To determine the role of tumor necrosis factor alpha (TNF-alpha) and Fas ligand (FasL, CD95L) in superantigen-induced and endotoxin-induced liver injury.


BACKGROUND
Gram-positive bacteria are increasingly common causes of sepsis and multiorgan failure, but the pathophysiologic mechanisms of superantigen-provoked hepatotoxicity remain elusive.


METHODS
Intravital fluorescence microscopy was used to study the liver microcirculation in mice challenged with superantigen (staphylococcal enterotoxin A, SEA) or endotoxin (lipopolysaccharide, LPS) combined with D-galactosamine.


RESULTS
Administration of 10 microg LPS and 50 microg SEA caused similar hepatocellular damage as determined by liver enzymes and apoptosis. Notably, TNF-alpha-deficient mice were completely protected against hepatic injury provoked by LPS, whereas no protection was observed in response to SEA. On the other hand, FasL-deficient mice were protected against liver injury induced by SEA, but no protection was found when challenged with LPS. LPS increased clear-cut leukocyte recruitment, whereas SEA had no significant effect on leukocyte responses in the liver microcirculation. Leukocyte responses to LPS were decreased by >56% in TNF-alpha gene-targeted animals. Moreover, antiadhesive therapy, ie, immunoneutralization of P-selectin, which is an effective inhibitor of leukocyte recruitment, protected against LPS-induced but not against SEA-induced hepatic damage.


CONCLUSIONS
These novel findings demonstrate that the mechanisms of hepatic injury in endotoxin-induced and superantigen-induced sepsis are principally different. On one hand, SEA-provoked hepatotoxicity is mediated by FasL and is not associated with leukocyte recruitment. On the other hand, liver damage provoked by LPS is mediated by TNF-alpha and characterized by prominent leukocyte responses. These data may facilitate development of more specific therapies against sepsis of different origins.
Klintman
Daniel
D
Department of Surgery, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
Li
Xiang
X
Sato
Tohru
T
Wang
Yusheng
Y
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D004768:Enterotoxins / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D053222:Fas Ligand Protein; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018089:Superantigens / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
D004768:Enterotoxins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C026066:enterotoxin A, Staphylococcal