losartan-potassium and Liver-Diseases--Alcoholic

The purpose of this study was to test for the presence of liver hypoxia and recovery after reperfusion when blood alcohol levels (BAL) are high. Male rats were fed ethanol intragastrically at a constant rate for 1 month. The pO(2) levels were then measured on the liver surface of these rats, in vivo during laparatomy under isoflurane anesthesia. To measure the response to acute hypoxia, the hepatic blood flow was clamped off at the porta hepatis. When the clamp was released, recovery from hypoxia was measured. A number of hypoxic-inducible genes in the liver were analyzed by means of quantitative RT-PCR as a measure of increased activation of hypoxia initiated transcription. The mRNA levels of genes for adrenomedullin, adrenergic receptor alpha, 1a and 1d, CDK inhibitor 1a, and erythropoietin were all significantly higher at the peaks than troughs. Expression of these same genes in the livers of control rats fed dextrose was lower than at the troughs. Although the mRNA level of the hypoxia-inducible factor (HIF-1alpha) was higher at the trough than at the peak, its protein concentration in the nuclear fraction was not increased at the troughs compared with the peaks. In fact, the nuclear protein level of HIF-1alpha at the peak was significantly higher than in control samples, which is consistent with the presence of hypoxia at the peaks. Further analysis of the HIF-alpha degradation regulation revealed that prolyl 4-hydroxylase (P4ha1) and von Hippel-Lindau syndrome homolog (Vhl) were both up-regulated at the troughs compared with the peaks. The liver surface oxygen levels at the peaks were reduced compared with the control samples. The pO(2) levels fell abruptly when the vessels at the porta hepatis were clamped. When the clamp was removed, allowing reperfusion of the liver, pO(2) returned to baseline levels in the control, and at the troughs but not at the peaks. These results support the hypothesis that hypoxia occurs at the peaks of the BAL cycle and recovery from ischemia is impaired at the peaks.

Topics: Administration, Oral; Adrenomedullin; Animals; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Erythropoietin; Ethanol; Hypoxia; Liver; Liver Diseases, Alcoholic; Male; Oligonucleotide Array Sequence Analysis; Oxygen; Peptides; Rats; Rats, Wistar; Receptors, Adrenergic; Reperfusion Injury; RNA, Messenger

The anemia of chronic disease is mediated by the cytokines that modulate the immune response, such as tumor necrosis factor (TNF) and gamma-interferon (gamma-IFN), and is associated with a blunted serum erythropoietin (sEPO) response to anemia. Previous reports suggest that patients with liver disease (LD) also exhibit a blunted sEPO response to anemia, and that patients with alcoholic LD had altered cytokines, including elevated TNF levels. To investigate the pathogenesis of anemia in alcoholic LD, sEPO, TNF, and gamma-IFN levels were determined in patients who had participated in a Department of Veterans Affairs Cooperative study of alcoholic LD.. sEPO, serum TNF-alpha, and serum gamma-IFN levels were evaluated in 40 patients with severe biopsy-proven alcoholic LD whose serum had been stored during the Department of Veterans Affairs Cooperative Study 275, and in 18 patients with iron deficiency (controls).. Mean hemoglobin (Hgb) was 11.2 +/- 0.3 g/dl for LD patients versus 11.4 +/- 0.4 g/dl for controls (p = 0.84). sEPO levels measured by ELISA were 29.6 +/- 4.1 units/liter in LD patients versus 25.4 +/- 5.4 units/liter in controls (p = 0.64). In both sets of patients, sEPO and Hgb were inversely related; the slopes of the two regression lines did not differ significantly (p = 0.92). TNF was detected in 3 of 40 LD patients and in 0 of 18 iron-deficient patients. Detection of TNF did not correlate with sEPO or Hgb, but did correlate strongly with severe caloric malnutrition (marasmus) and mortality at 6 months (p = 0.049 and 0.04, respectively). gamma-IFN was not detected.. These findings indicate that the sEPO response is preserved in patients with severe alcoholic LD, and suggest that anemia in LD arises from different mechanisms than does the anemia of chronic disease. TNF production in severe alcoholic LD is strongly correlated with caloric malnutrition and mortality.

Topics: Anemia; Anemia, Iron-Deficiency; Combined Modality Therapy; Cytokines; Erythropoietin; Hemoglobinometry; Humans; Liver Diseases, Alcoholic; Nutritional Status; Protein-Energy Malnutrition; Reference Values; Tumor Necrosis Factor-alpha