TNF-alpha dependent production of inducible nitric oxide is involved in PGE(1) protection against acute liver injury

• Published in: Gut Vol. 47; no. 4; p. 553
• Main Authors: Muntané, J, Rodríguez, F J, Segado, O, Quintero, A, Lozano, J M, Siendones, E, Pedraza, C A, Delgado, M, O'Valle, F, García, R, Montero, J L, De La Mata, M, Miño, G
• Format: Journal Article
• Language: English
• Published: England 01.10.2000
• Subjects: Alanine Transaminase - blood; Alprostadil - metabolism; Animals; Antibodies - immunology; Galactosamine; Liver Failure, Acute - chemically induced; Liver Failure, Acute - metabolism; Male; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0017-5749
• DOI: 10.1136/gut.47.4.553

Tumour necrosis factor alpha (TNF-alpha) and nitric oxide modulate damage in several experimental models of liver injury. We have previously shown that protection against D-galactosamine (D-GalN) induced liver injury by prostaglandin E(1) (PGE(1)) was accompanied by an increase in TNF-alpha and nitrite/nitrate in serum. The aim of the present study was to evaluate the role of TNF-alpha and nitric oxide during protection by PGE(1) of liver damage induced by D-GalN. Liver injury was induced in male Wistar rats by intraperitoneal injection of 1 g/kg of D-GalN. PGE(1) was administered 30 minutes before D-GalN. Inducible nitric oxide synthase (iNOS) was inhibited by methylisothiourea (MT), and TNF-alpha concentration in serum was lowered by administration of anti-TNF-alpha antibodies. Liver injury was evaluated by alanine aminotransferase activity in serum, and histological examination and DNA fragmentation in liver. TNF-alpha and nitrite/nitrate concentrations were determined in serum. Expression of TNF-alpha and iNOS was also assessed in liver sections. PGE(1) decreased liver injury and increased TNF-alpha and nitrite/nitrate concentrations in serum of rats treated with D-GalN. PGE(1) protection was related to enhanced expression of TNF-alpha and iNOS in hepatocytes. Administration of anti-TNF-alpha antibodies or MT blocked the protection by PGE(1) of liver injury induced by D-GalN. This study suggests that prior administration of PGE(1) to D-GalN treated animals enhanced expression of TNF-alpha and iNOS in hepatocytes, and that this was causally related to protection by PGE(1) against D-GalN induced liver injury.