Protective effect of rhIL-11 in a murine model of acetaminophen-induced hepatotoxicity.
Acetaminophen intoxication results in hepatotoxicity associated with increased serum concentrations of hepatocellular leakage enzymes such as aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase, centrilobular degeneration and necrosis, and activation of Kupffer cells. Recombinant human Interleukin-11 (rhIL-11) downregulates the production of proinflammatory mediators from activated macrophages and has direct effects on hepatocyte gene expression. Based on these biological activities of rhIL-11, the effect of pretreatment with rhIL-11 in a murine model of acetaminophen-induced hepatotoxicity was examined. Administration of 500 microg/kg acetaminophen to B6C3F1 mice resulted in progressive hepatotoxicity as demonstrated by elevated serum concentrations of hepatocellular leakage enzymes and TNFalpha and histopathology. Pretreatment with 250 or 500 microg/kg of subcutaneously administered rhIL-11 2 hours before acetaminophen administration reduced serum concentrations of hepatocellular leakage enzymes and TNFalpha by 40-50%. This was associated with a statistically significant decrease in mean severity score for centrilobular hemorrhage and necrosis from grade 3 to grade 2 for rhIL-11-treated animals compared to vehicle. These results indicate that treatment with rhIL-11 has a protective effect in a model of acetaminophen-induced liver damage.
Trepicchio
W L
WL
Department of Molecular Medicine Genetics Institute/Wyeth Research, Andovter, Massachusetts 01810, USA.
Bozza
M
M
Bouchard
P
P
Dorner
A J
AJ
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007279:Injections, Subcutaneous; D017370:Interleukin-11 / Q000008:administration & dosage / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017370:Interleukin-11; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C105308:oprelvekin