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

Background-Tumour necrosis factor a (TNF-alpha) and nitric oxide modulate d amage in several experimental models of liver injury. We have previously sh own that protection against D-galactosamine (D-GalN) induced liver injury b y prostaglandin E-1 (PGE(1)) was accompanied by an increase in TNF-alpha an d nitrite/nitrate in serum. Aims-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 . Methods-Liver injury was induced in male Wistar rats by intraperitoneal inj ection of 1 g/kg of D-GalN. PGE(1) was administered 30 minutes before D-Gal n. Inducible nitric oxide synthase (MOS) was inhibited by methylisothiourea (MT), and TNF-alpha concentration in serum was lowered by administration o f anti-TNF-alpha antibodies. Liver injury was evaluated by alanine aminotra nsferase activity in serum, and histological examination and DNA fragmentat ion in liver. TNF-alpha and nitrite/nitrate concentrations were determined in serum. Expression of TNF-alpha and iNOS was also assessed in liver secti ons. Results-PGE(1) decreased liver injury and increased TNF-alpha and nitrite/n itrate concentrations in serum of rats treated with D-GalN. PGE(1) protecti on was related to enhanced expression of TNF-alpha and iNOS in hepatocytes. Administration of anti-TNF-alpha antibodies or MT blocked the protection b y PGE(1) of liver injury induced by D-GalN. Conclusions-This study suggests that prior administration of PGE, to D-Galn treated animals enhanced expression of TNF-alpha and iNOS in hepatocytes, and that this was causally related to protection by PGE, against D-GalN ind uced liver injury.