HISTOPATHOLOGY OF ACETAMINOPHEN-INDUCED LIVER CHANGES - ROLE OF INTERLEUKIN-1-ALPHA AND TUMOR-NECROSIS-FACTOR-ALPHA

Administration of 500 mg/kg acetaminophen (APAP) to female B6C3F1 mice resulted in well-documented pathophysiological changes in the liver m anifested as increased serum concentration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, an d serum sorbitol dehydrogenase), centrilobular congestion, and hepatoc ellular degeneration and necrosis. The role of proinflammatory cytokin es, including tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha (IL-1 alpha), on the hepatotoxicity of APAP was examined at 4, 8, 12, and 24 hr following APAP administration. Neutralization of TNF -alpha or IL-1 alpha with specific antibodies partially prevented the hepatotoxic effects of APAP at the 4- and 8-hr time points. In additio n, prior administration of anti-TNF-alpha antibodies shortened the rec overy time following APAP treatment. While IL-I receptor antagonist (I L-1ra) had only a modest protective effect against APAP-induced liver damage, as determined by serum enzyme release, IL-1ra had no effect on the degree of hepatic congestion or necrosis at any of the time point s examined. On the other hand, administration of antibodies against IL -lra exacerbated APAP-induced liver toxicity. These results suggest th at TNF-alpha and IL-1 alpha play an important role in the degree of da mage and recovery that the Liver undergoes following APAP intoxication .