Protective Effect of rhIL-11 in a Murine Model of Acetaminophen-Induced Hepatotoxicity

Abstract

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 proinfl ammatory 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-induce d hepatotoxicity was examined. Administration of 500 ug/kg acetaminophen to B6C3F1 mice resulted in progressive hepatotoxicity as demonstrated by elevated serum concentration s of hepatocellular leakage enzymes and TNFα and histopathology. Pretreatment with 250 or 500 ug/kg of subcutaneously administered rhIL-11 2 hours before acetaminophen administration reduced serum concentrations of hepatocellular leakage enzyme s and TNFα by 40—50%. This was associated with a statistically significant decreas e in mean severity score for centrilobular hemorrhag e 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-induce d liver damage.

Keywords

Acetaminophen cytokine inflammation interleukin-11 liver damage.

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