TNF-α dependent production of inducible nitric oxide is involved in PGE1 protection against acute liver injury

• Published in: Gut Vol. 47; no. 4; pp. 553 - 562
• 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: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01-10-2000; BMJ
• Subjects: Biological and medical sciences; d-galactosamine; Digestive system; Investigative techniques, diagnostic techniques (general aspects); liver injury; Medical sciences; methylisothiourea; nitric oxide; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; prostaglandin E1; tumour necrosis factor α; Rat; Acute; Liver; Cytokine; Rodentia; Hepatic disease; Prostaglandin E1; Experimental study; Electron microscopy; Pathology; Vertebrata; Mammalia; Association; Animal; Nitric oxide; Digestive diseases; Lesion; Mechanism of action; Tumor necrosis factor α
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.47.4.553

BACKGROUND Tumour necrosis factor α (TNF-α) 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 E1 (PGE1) was accompanied by an increase in TNF-α and nitrite/nitrate in serum. AIMS The aim of the present study was to evaluate the role of TNF-α and nitric oxide during protection by PGE1 of liver damage induced by D-GalN. METHODS Liver injury was induced in male Wistar rats by intraperitoneal injection of 1 g/kg of D-GalN. PGE1 was administered 30 minutes before D-GalN. Inducible nitric oxide synthase (iNOS) was inhibited by methylisothiourea (MT), and TNF-α concentration in serum was lowered by administration of anti-TNF-α antibodies. Liver injury was evaluated by alanine aminotransferase activity in serum, and histological examination and DNA fragmentation in liver. TNF-α and nitrite/nitrate concentrations were determined in serum. Expression of TNF-α and iNOS was also assessed in liver sections. RESULTS PGE1decreased liver injury and increased TNF-α and nitrite/nitrate concentrations in serum of rats treated with D-GalN. PGE1protection was related to enhanced expression of TNF-α and iNOS in hepatocytes. Administration of anti-TNF-α antibodies or MT blocked the protection by PGE1 of liver injury induced by D-GalN. CONCLUSIONS This study suggests that prior administration of PGE1 to D-GalN treated animals enhanced expression of TNF-α and iNOS in hepatocytes, and that this was causally related to protection by PGE1against D-GalN induced liver injury.