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

Abstract

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-Ga1N) 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-Ga1N. Methods - Liver injury was induced in male Wistar rats by intraperitoneal injection of 1 g/kg of D-Ga1N. PGE1 was administered 30 minutes before D-Ga1N. 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 - PGE1 decreased liver injury and increased TNF-α and nitrite/nitrate concentrations in serum of rats treated with D-Ga1N. PGE1 protection was related to enhanced expression of TNF-α and iNOS in hepatocytes. Administration of anti-TNF-α antibodies or NIT blocked the protection by PGE1 of liver injury induced by D-Ga1N. Conclusions - This study suggests that prior administration of PGE1 to D-Ga1N treated animals enhanced expression of TNF-α and iNOS in hepatocytes, and that this was causally related to protection by PGE1 against D-Ga1N induced liver injury.