losartan-potassium and Liver-Failure--Acute

Fulminant hepatic failure is a severe clinical syndrome associated with a high rate of patient mortality. Recent studies have shown that in addition to its hematopoietic effect, erythropoietin (EPO) has multiple protective effects and exhibits antiapoptotic, antioxidant and anti-inflammatory activities. The present study aimed to determine the hepatoprotective effect of EPO and to elucidate the underlying mechanisms using a D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced model of acute liver injury. Experimental groups of mice were administered with various doses of EPO (1,000, 3,000 or 10,000 U/kg, intraperitoneal) once per day for 3 days, prior to injection with D-GalN (700 mg/kg)/LPS (10 µg/kg). Mice were sacrificed 8 h after treatment with D‑GalN/LPS. Liver function and histopathology, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px) activities and EPO receptor (EPOR) and phosphatidylinositol 3-kinase (PI3K) mRNA expression were evaluated. D-GalN/LPS administration markedly induced liver injury, as evidenced by elevated levels of serum aminotransferases, as well as histopathological changes. Compared with the D-GalN/LPS group, pretreatment with EPO significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase and MDA, and increased the activities of SOD and GSH-Px. Furthermore, the protective effects of EPO were paralleled by an upregulation in the mRNA expression of EPOR and PI3K. These data suggest that EPO can ameliorate D-GalN/LPS-induced acute liver injury by reducing oxidative stress and upregulating the mRNA expression of EPOR and PI3K.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Galactosamine; Glutathione Peroxidase; Lipopolysaccharides; Liver; Liver Failure, Acute; Malondialdehyde; Mice; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinase; Protective Agents; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; Superoxide Dismutase

Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), d-galactosamine (GalN)-induced FHF is a well-established model of liver injury in mice. Erythropoietin has a powerful tissue-protective effect in animal models. The aim of this study was to investigate the effect and mechanism of recombinant human erythropoietin (rhEPO) administration in FHF mice.. C57BL/6 (n=42) mice were studied in vivo in a fulminant model induced by GalN/LPS. rhEPO was administered 30 min after the induction of FHF. Serum liver enzymes and hepatic tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were determined. Histologic analysis was performed, and apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor (NF)-κB and c-Jun-N-terminal kinase (JNK) activation were studied using Western blot analysis.. After the induction of FHF, all control mice died within 12 hr of GalN/LPS administration. However, 83% of mice that were administered rhEPO were alive 2 weeks later, and overall survival improved (Kaplan-Meier, P<0.001). The serum liver enzymes, hepatic TNF-α and IL-1β levels, liver histologic injury, and apoptotic hepatocytes were significantly reduced in FHF mice that were administered rhEPO compared with untreated mice. A significant decrease in hepatic NF-κB and JNK activation was noted in FHF rhEPO-treated mice compared with FHF untreated mice.. The administration of rhEPO brought about increased survival and attenuation of the hepatic injury. This was associated with decreased hepatic NF-κB and JNK activation and thus TNF-α and IL-1β levels. These findings have important implications for the potential use of rhEPO in FHF.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Disease Models, Animal; Erythropoietin; Galactosamine; Humans; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Kaplan-Meier Estimate; Lipopolysaccharides; Liver; Liver Failure, Acute; Mice; Mice, Inbred C57BL; NF-kappa B; Recombinant Proteins; Tumor Necrosis Factor-alpha

In many liver disorders inflammation and apoptosis are important pathogenic components, finally leading to acute liver failure. Erythropoietin and its analogues are known to affect the interaction between apoptosis and inflammation in brain, kidney, and myocardium. The present study aimed to determine whether these pleiotropic actions also exert hepatoprotection in a model of acute liver injury. C57BL/6J mice were challenged with d-galactosamine (Gal) and Escherichia coli lipopolysaccharide (LPS) and studied 6 hours thereafter. Animals were either pretreated (24 hours before Gal-LPS exposure) or posttreated (30 minutes after Gal-LPS exposure) with darbepoetin-alpha (DPO, 10 mug/kg i.v.). Control mice received physiological saline. Administration of Gal-LPS caused systemic cytokine release and provoked marked hepatic damage, characterized by leukocyte recruitment and microvascular perfusion failure, caspase-3 activation, and hepatocellular apoptosis as well as enzyme release and necrotic cell death. DPO-pretreated and -posttreated mice showed diminished systemic cytokine concentrations, intrahepatic leukocyte accumulation, and hepatic perfusion failure. Hepatocellular apoptosis was significantly reduced by 50 to 75% after DPO pretreatment as well as posttreatment. In addition, treatment with DPO also significantly abrogated necrotic cell death and liver enzyme release. In conclusion, these observations may stimulate the evaluation of DPO as hepatoprotective therapy in patients with acute liver injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Caspase 3; Cytokines; Darbepoetin alfa; Erythropoietin; Galactosamine; Hematinics; Inflammation; Lipopolysaccharides; Liver; Liver Failure, Acute; Male; Mice; Mice, Inbred C57BL; Proliferating Cell Nuclear Antigen