Role of nitric oxide in D-galactosamine-induced cell death and its protection by PGE1 in cultured hepatocytes.
Prostaglandin E(1) (PGE(1)) reduces cell death in experimental and clinical manifestations of liver dysfunction. Nitric oxide (NO) has been shown to exert a protective or noxious effect in different experimental models of liver injury. The aim of the present study was to investigate the role of NO during PGE(1) protection against D-galactosamine (D-GalN) citotoxicity in cultured hepatocytes. PGE(1) was preadministered to D-GalN-treated hepatocytes. The role of NO in our system was assessed by iNOS inhibition and a NO donor. Different parameters related to apoptosis and necrosis, NO production such as nitrite+nitrate (NO(x)) release, iNOS expression, and NF-kappaB activation in hepatocytes were evaluated. The inhibition of iNOS reduced apoptosis induced by D-GalN in hepatocytes. PGE(1) protection against D-GalN injury was associated with its capacity to reduce iNOS expression and NO production induced by D-GalN. Nevertheless, iNOS inhibition showed that protection by PGE(1) was also mediated by NO. Low concentrations of a NO donor reduced D-GalN injury with a decrease in the extracellular NO(x) concentration. High concentrations of the NO donor enhanced NO(x) concentration and increased cell death by D-GalN. The present study suggests that low NO production induced by PGE(1) preadministration reduces D-GalN-induced cell death through its capacity to reduce iNOS expression and NO production caused by the hepatotoxin.
Siendones
Emilio
E
Unidad de Investigación, Servicio Aparato Digestivo, Hospital Universitario Reina Sofi;a, Av. Menéndez Pidal s/n, E-14004, Córdoba, Spain.
Fouad
Dalia
D
Abou-Elella
Amira Mohamed Kamal ElSaid
AM
Quintero
Ana
A
Barrera
Pilar
P
Muntané
Jordi
J
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000032:analysis / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D024202:Electrophoretic Mobility Shift Assay; D005688:Galactosamine / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011458:Prostaglandins E / Q000378:metabolism / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D051017:Apoptosis Regulatory Proteins; C091572:DAP protein, human; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D011458:Prostaglandins E; D011506:Proteins; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D005688:Galactosamine; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010396:Penicillamine