Curcumin attenuates oxidative stress and inflammatory response in the early phase after partial hepatectomy with simultaneous intraabdominal infection in rats.

BACKGROUND: Curcumin is a nontoxic, hepatoprotective antioxidant. It has been shown to efficiently scavenge oxygen free radicals, increase intracellular glutathione concentrations, and prevent lipid peroxidation in rat hepatocytes. Moreover, it has strong anti-inflammatory effects. In the present study we assessed its effect in a model of liver regeneration impaired by bacterial infections. MATERIAL AND METHODS: Male Sprague-Dawley rats underwent sham operation, cecal ligation and puncture (CLP), synchronous partial hepatectomy (PH), and CLP or synchronous PH+CLP with perioperative application of curcumin (100 mg per kg bodyweight per d) 48 h before surgery. Rats were sacrificed 24 h after surgery. Liver function was analyzed by measuring the serum albumin, serum bilirubin, and bile production. The local inflammatory response in the liver tissue was evaluated by quantification of TNF-alpha, IL-6 mRNA, and quantification of IL-1beta by ELISA. In addition, hepatic concentrations of reduced glutathione (GSH) and the oxidized disulfide dimer of glutathione (GSSG) were measured for determination of the redox state. RESULTS: After simultaneous PH+CLP curcumin significantly reduced the expression of TNF-alpha and IL-6 mRNA in the liver tissue. The IL-1beta concentration in the liver was also slightly, but not significantly, lower in the curcumin group. A severe depletion of hepatic glutathione was found in the PH+CLP group. This was reversed by curcumin application, after which the GSH to GSSG ratio increased markedly. The hepatocellular damage, measured by ALT liberation, was significantly lower in the curcumin treated group. The relative liver weight in the curcumin group was significantly higher 24 h after PH+CLP. However, hepatocellular proliferation parameters were not significantly improved by antioxidative treatment with curcumin. Only the Ki-67 index was slightly higher in the curcumin treated PH+CLP group (14+/-3%) than in the untreated PH+CLP group (7%+/-3%). The hepatocyte density was significantly lower in the curcumin group than in the corresponding untreated group. CONCLUSION: In the present model, curcumin revealed significant hepatoprotective effects with stabilization of redox state, reduced liberation of liver enzymes, and attenuated expression of pro-inflammatory cytokines. However, the hepatocellular proliferation was not significantly influenced.

Synergistic effect of erythropoietin but not G-CSF in combination with curcumin on impaired liver regeneration in rats.

INTRODUCTION: The effect of erythropoietin (Epo) and granulocyte colony-stimulating factor (G-CSF) alone or in combination with the hepatoprotective antioxidant curcumin (Cur) was evaluated in a model of delayed liver regeneration. MATERIALS AND METHODS: Sprague Dawley rats underwent 70% liver resection with simultaneous cecal ligation and puncture and were randomised to five groups: no treatment, G-CSF (100 microg/kg), Epo (1,000 IU/kg), each alone or in combination with Cur (100mg/kg). Twenty-four hours after surgery, blood and tissue samples were collected. Markers of liver regeneration (liver weight, mitotic index, Ki-67 index), function (bilirubin, bile flow) and hepatocellular damage (liver enzymes, histomorphology) were determined. In addition, cytokine expression and hepatic glutathione concentrations were measured. RESULTS: Liver regeneration was not improved by G-CSF or Epo monotherapy. Epo more effectively increased liver weight and regeneration markers, but the difference was not significant. Whereas liver regeneration was slightly inhibited in the G-CSF plus Cur group, Epo plus Cur significantly improved liver regeneration. This was accompanied by reduced oxidative stress. Liver function and the expression of pro-inflammatory cytokines were comparable in all treatment groups. CONCLUSION: In the present model, Epo, at a relatively low dosage, did not improve liver regeneration. However, the combination of Epo and Cur showed a synergistic effect with highly significant stimulation of liver regeneration.

Intraabdominal bacterial infections significantly alter regeneration and function of the liver in a rat model of major hepatectomy.

BACKGROUND: No systematic investigations of interactions of postoperative infections and liver regeneration after resection are available. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent sham operation, 70% partial hepatectomy (PH), cecal ligation and puncture (CLP), or synchronous PH + CLP and were killed at regular intervals. Liver regeneration and function were measured by the mitotic index, Bromo-deoxy-uridine labeling, and Ki-67 as well as bilirubin, albumin, and indocyanine green plasma disappearance rate. The inflammatory response was evaluated by determination of IL-1beta and myeloperoxidase (MPO) activity. Bacterial concentrations in different organs were quantified. RESULTS: Simultaneous CLP + PH resulted in a significantly delayed regeneration kinetic, which was most pronounced at 24 h. This was preceded by hyperinflammation with increased liberation of pro-inflammatory cytokines in the PH + CLP group at 6 h. After 48 h, the pro-inflammatory response declined, and regeneration proceeded also in the PH + CLP group. Liver function was found impaired in both groups; however, it was significantly worse in the PH + CLP group. Especially after 48 h, when regeneration peaked in this group, liver function significantly declined. At 96 h, only minor differences were seen, but the persistently elevated proliferative activity indicated the delay of regeneration after PH + CLP. CONCLUSION: The present analysis shows that infectious conditions delay liver regeneration. Our data suggest a cross-linkage of both conditions via the functional liver capacity. A direct role of microorganisms seems unlikely; however, the inhibitory effect of the pro-inflammatory cytokines may be involved.