title: Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis.
abstract: Paracetamol-induced hepatic necrosis is the most common form of toxic liver injury experienced in clinical practice in the UK and USA. Recently, reports have described prevention of hepatic necrosis, induced by other hepato-toxins, by inhibiting tumour necrosis factor alpha (TNFalpha). The aim of the present study was to determine the role of TNFalpha in paracetamol-induced hepatic necrosis. Six-week-old CBA/J female mice were given 300 mg/kg paracetamol by intraperitoneal (IP) injection after an 8-h fast. Hepatic expression of TNFalpha was measured by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR). Serum TNFalpha was measured by ELISA. One hour prior to paracetamol injection, mice were also given blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, interleukin 10 (IL-10), and dexamethasone. Hepatic injury was measured by serum aspartate aminotransferase and histological assessment on haematoxylin and eosin (H&E)-stained liver sections. There was a significant increase in serum TNFalpha at 6 h (control 0.002+/-0.002 ng/ml, n=7; paracetamol-treated 0.022+/-0.007 ng/ml, n=5, p<0.05), but hepatic TNFalpha expression did not change up to 24 h following paracetamol injection. Histologically severe centrilobular hepatic necrosis was noted at 3 h and progressed for 24 h after paracetamol poisoning. Death rate, serum aspartate aminotransferase, and hepatic histology were not significantly different between the groups treated with blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, IL-10, and dexamethasone, compared with controls. In conclusion, there is no evidence to suggest that modulation of TNFalpha expression affects hepatic injury following experimental paracetamol poisoning; anti-TNFalpha therapies are therefore unlikely to be effective in the corresponding clinical situation.
authors.affiliation: Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh, UK. ksimp@srvl.med.ed.ac.uk
authors.forename: K J
authors.initials: KJ
authors.lastname: Simpson
authors.forename: N W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: A H
authors.initials: AH
authors.lastname: McGregor
authors.forename: D J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008808:Mice, Inbred CBA; D009336:Necrosis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018712:Analgesics, Non-Narcotic; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D001219:Aspartate Aminotransferases