Impaired liver regeneration following partial hepatectomy using the Pringle maneuver: Protective effect of mesna.
ABSTRACT We investigated the role of the prophylactic administration of the antioxidant 2-mercaptoethane sulfonate (mesna) on the hepatocyte-regenerating capacity following partial hepatectomy (PH) with concurrent Pringle maneuver.
Wistar rats were subjected to PH (70% hepatectomy), 30 min Pringle maneuver, PH plus Pringle with or without mesna pretreatment (400 mg/kg, per os, 3 h before Pringle), or sham operation. At 24 h, 48 h, 72 h, and 1 week after operation, relative liver weight, hepatocyte mitotic activity (mitotic index), the histopathological score and serum aspartate aminotransferase, and alanine aminotransferase concentrations were assessed. At 1 h after operation, oxidative stress markers (glutathione to glutathione disulfide ratio, malondialdehyde concentration, and superoxide dismutase activity) and nuclear factor-kappaB (NF-kappaB) activity were assessed.
Hepatectomy stimulated the regenerating process and induced mild oxidative stress and the activation of NF-kappaB in hepatocytes, while causing tissue injury in the remnant liver. When PH was performed under Pringle maneuver, hepatocyte mitotic activity was substantially suppressed, although Pringle alone initiated a delayed regenerating response. Furthermore, Pringle maneuver deteriorated oxidative stress markers, markedly increased NF-kappaB activity, and aggravated tissue injury, as compared to hepatectomy alone. Mesna pretreatment prevented the Pringle-induced antimitotic effect and the induction of oxidative stress, inhibited the activation of NF-kappaB, while attenuating liver injury after PH under Pringle.
The excessive activation of NF-kappaB is related to the suppression of hepatocyte-regenerating activity following PH with concurrent liver ischemia. Mesna pretreatment protects the liver against the Pringle-induced antimitotic effect after PH via the prevention of oxidative stress and the inhibition of NF-kappaB activation.
- [Show abstract] [Hide abstract]
ABSTRACT: Large volume radiofrequency ablation (RFA) of the liver disrupts intestinal mucosa barrier with subsequent bacterial translocation. To investigate the effect of the Pringle maneuver applied concurrently with extended liver RFA on gut barrier integrity and bacterial translocation. Rats were subjected to 30% liver RFA following laparotomy (group RFA), RFA plus 30 min Pringle (group RFA + P), Pringle (group P) or sham operation (group S). Intestinal tissue specimens were excised for histopathological examination and assessment of mucosal morphometry, apoptotic activity, mitotic activity and oxidative state. Tissue specimens were collected from the mesenteric lymph nodes, non-ablated liver parenchyma, kidneys and lungs for bacterial culture. Blood samples were collected from the portal and systemic circulation for endotoxin level measurement. In group RFA + P, intestinal histopathologic lesions, mucosal atrophy and crypt cell apoptosis were more prominent compared to group RFA. Mitotic activity was suppressed. Oxidative stress was equally induced in all experimental groups. The incidence of positive bacterial cultures, bacterial counts and endotoxin levels were higher in group RFA + P compared to the other groups. The application of the Pringle maneuver concurrently with extended liver RFA aggravates gut barrier dysfunction with more aggressive translocation of endotoxins and intestinal bacteria.Digestive Diseases and Sciences 10/2010; 56(5):1548-56. · 2.26 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The objectives of the present study were to test the hypothesis that hepatocyte regenerating activity induced by radiofrequency ablation (RFA) of the liver is attenuated when performed under Pringle maneuver, and to investigate the potentially protective effect of mesna prophylactic administration. Wistar rats were subjected to liver RFA (group RFA), RFA plus Pringle maneuver for 30 min (group RFA+P), RFA plus Pringle plus mesna (400mg/kg, per os, 3h prior to operation) (group RFA+P+M), Pringle only (group P), or sham operation (group S) after midline laparotomy. At 1h, liver oxidative state (glutathione to glutathione disulfide ratio-GSH/GSSG) and nuclear factor κB (NF-κB) activity were assessed in liver specimens. At 1, 3, and 6h, the levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured in blood serum. At 24h, 48 h, 1 wk, and 3 wk, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured in blood serum and the histopathologic profile and hepatocyte mitotic activity were assessed in liver specimens. Mitotic activity was low but sustained in groups RFA and RFA+P+M, more intense in group P, while suppressed in group RFA+P. Histopathologic profile was deteriorated with lesions being more intense in group RFA+P but significantly less severe in group RFA+P+M. Oxidative stress was equally induced in all experimental groups. NF-κB was activated in groups RFA, RFA+P, and P, but not in group RFA+P+M. IL-6 and TNF-α serum levels were increased; the levels were significantly higher in group RFA+P, while lower in group RFA+P+M. Serum transaminases levels were increased during the first 48 h. Hepatocyte regenerating activity is suppressed following liver RFA under Pringle maneuver. Prophylactic administration of mesna preserves hepatocyte regenerating capacity by attenuating acute inflammatory response and minimizing hepatic tissue injury in the non-ablated liver parenchyma.Journal of Surgical Research 07/2011; 169(1):44-50. · 2.02 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Vascular occlusion to prevent haemorrhage during liver resection causes ischaemia-reperfusion (IR) injury. Insights into the mechanisms of IR injury gathered from experimental models have contributed to the development of therapeutic approaches, some of which have already been tested in randomized clinical trials. The review was based on a PubMed search using the terms 'ischemia AND hepatectomy', 'ischemia AND liver', 'hepatectomy AND drug treatment', 'liver AND intermittent clamping' and 'liver AND ischemic preconditioning'; only randomized controlled trials (RCTs) were included. Twelve RCTs reported on ischaemic preconditioning and intermittent clamping. Both strategies seem to confer protection and allow extension of ischaemia time. Fourteen RCTs evaluating pharmacological interventions, including antioxidants, anti-inflammatory drugs, vasodilators, pharmacological preconditioning and glucose infusion, were identified. Several strategies to prevent hepatic IR have been developed, but few have been incorporated into clinical practice. Although some pharmacological strategies showed promising results with improved clinical outcome there is not sufficient evidence to recommend them.British Journal of Surgery 10/2010; 97(10):1461-75. · 4.84 Impact Factor