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Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol‐induced hepatic necrosis
Author(s) -
Simpson Kenneth J.,
Lukacs Nicholas W.,
McGregor Angus H.,
Harrison David J.,
Strieter Robert M.,
Kunkel Steven L.
Publication year - 2000
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/(sici)1096-9896(200003)190:4<489::aid-path534>3.0.co;2-v
Subject(s) - necrosis , tumor necrosis factor alpha , medicine , alpha (finance) , pathology , surgery , construct validity , patient satisfaction
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 (TNFα). The aim of the present study was to determine the role of TNFα 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 TNFα was measured by enzyme‐linked immunoassay (ELISA) and reverse transcriptase‐polymerase chain reaction (RT‐PCR). Serum TNFα was measured by ELISA. One hour prior to paracetamol injection, mice were also given blocking anti‐TNFα antibodies, soluble TNFα 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 TNFα 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 TNFα 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‐TNFα antibodies, soluble TNFα receptor, IL‐10, and dexamethasone, compared with controls. In conclusion, there is no evidence to suggest that modulation of TNFα expression affects hepatic injury following experimental paracetamol poisoning; anti‐TNFα therapies are therefore unlikely to be effective in the corresponding clinical situation. Copyright © 2000 John Wiley & Sons, Ltd.