Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis

Paracetamol-induced hepatic necrosis is the most common form of toxic liver injury experienced in clinical practice in the UK and USA. Recently, repor ts have described prevention of hepatic necrosis, induced by other hepato-t oxins, by inhibiting tumour necrosis factor alpha (TNF alpha). The aim of t he present study was to determine the role of TNF alpha in paracetamol-indu ced hepatic necrosis, Six-week-old CBA/J female mice were given 300 mg/kg p aracetamol by intraperitoneal (IP) injection after an 8-h fast. Hepatic exp ression of TNF alpha was measured by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR), Serum TNF alpha w as measured by ELISA, One hour prior to paracetamol injection, mice were al so given blocking anti-TNF alpha antibodies, soluble TNF alpha receptor, in terleukin 10 (IL-10), and dexamethasone, Hepatic injury was measured by ser um aspartate aminotransferase and histological assessment on haematoxylin a nd eosin (H&E)-stained liver sections. There was a significant increase in serum TNF alpha at 6 h (control 0.002+/-0.002 ng/ml, n=7; paracetamol-treat ed 0.022+/-0.007 ng/ml, n=5, p<0.05), but hepatic TNF alpha expression did not change up to 24 h following paracetamol injection. Histologically sever e centrilobular hepatic necrosis was noted at 3 h and progressed for 24 h a fter paracetamol poisoning, Death rate, serum aspartate aminotransferase, a nd hepatic histology were not significantly different between the groups tr eated with blocking anti-TNF alpha antibodies, soluble TNF alpha receptor, IL-10, and dexamethasone, compared with controls, In conclusion, there is n o evidence to suggest that modulation of TNF alpha expression affects hepat ic injury following experimental paracetamol poisoning; anti-TNF alpha ther apies are therefore unlikely to be effective in the corresponding clinical situation. Copyright (C) 2000 John Wiley & Sons, Ltd.