Mechanism Research And Methods Against Excessive Inflammatory Reactions After Hepatectomy

Background and objectiveExcessive liver resection is the only hope of cure for extra-large and multiple occupying liver lesions. Most patients with liver occupying lesions often associated with other liver abnormalities such as cirrhosis. High surgical risk could be leading to fulminant hepatic failure that has a mortality rate up to 70% to 90%. Protection of the remnant liver function in the first 48h after surgery remains great challenge to the surgeons. The efficacy of various existing measures, including the artificial liver and other supporting methods, are limited. Our previous study in rat found that liver regeneration reaches to the highest level at 72 hours after resection. Animal will most likely survive if the regeneration could compensate for the first 48 hours. Therefore, to identify appropriate and effective measures to help the remnant liver to sustain through this risky period is particularly important. Our previous study found that application of cytokine signal transduction inhibitor AG490 and atorvastatin can inhibit the excessive inflammatory reaction of 90% hepatectomy in rats, reducing the excessive expression of many proinflammatory cytokines to body including a residual liver function damage; Ulinastatin can reduce the biological lipid membrane which interfere with th e binding with the receptor to achieve inhibiting the excessive inflammatory reactio n, and it can inhibit the release of proinflammatory cytokines from macrophages which can reduce the excessive inflammatory reaction of local and systemicorgan d amage. Whether AG90, atorvastatin or Ulinastatin, they are indications of drugs in other diseases,but they all demonstrated their protective effects on residual liver function from animal experiments and clinical trials, So we expand the mind, if there are more direct and effective drugs to liver function protection incommon hepatoprotective drugs? we have noticed that the MgIG, hoping to get more positive results from the study.Magnesium Isoglycyrrhizinate (MgIG), a hepatocyte protective agent, has been shown to have the effect of anti-inflammation, liver cell membrane protection, and liver function improvement. Efficacy studies showed that protective function of MgIG to the acute liver damage is induced by D-galactosamine. MgIG can decrease the serum level of transaminases, prevent liver cell degeneration, and reduce the incidence of necrosis and inflammatory cell infiltration. MgIG is especially effective in the treatment of chronic liver injury induced by carbon tetrachloride in rats,It also has a protective effect on immunological liver injury in mice induced by Gal/FCA by reducing inflammation and fibrosis, lowering the nitro-monoxide levels, and improving liver function.Most of the previous studies of MgIG have focused on chronic hepatitis, alcoholic cirrhosis, and drug-induced liver injury. A few researches mainly involved in surgical ischemia-reperfusion injury and liver regeneration. No publication was found for the anti-inflammatory effect of MgIG after liver resection.In order to clarify the magnesium isoglycyrrhizinate in perioperative period of protect the liver function and its mechanism, we designed this study, by using the standard 90% hepatectomy model in rats, which is a modified operation for Emond method. From preliminary experiments, we found that the mortality was 100% after 90% hepatectomy in rats in 24h. Using the standard 90% hepatectomy model was designed to cause the damage of liver function to test the corresponding treatment measures. This study has evaluated the magnesium isoglycyrrhizinate Protective effect to liver from the change of biochemical index and inflammatory cytokines in the peripheral blood, and has studied the residual liver tissue inflammation related signaling pathway by molecular biological methods. The purpose of this study is to elucidate the mechanism of MgIG in protecting liver function in molecular level. In this study, The purpose of this research is to investigate the mechanism of MgIG on protecting liver function from molecular level.Objective:It has been challenging to protect the remnant liver function after an excessive liver resection. This study was designed to investigate the protective effect of magnesium isoglycyrrhizinate (MgIG) on excessive hepatectomy animal modal and its possible mechanism..MethodSprague-Dawley (SD) rats with 90% liver resection were divided into three groups, and were injected intraperitoneally of with 3ml saline (control),30mg/kg (low-dose) and 60mg/kg (high-dose) of MgIG respectively. Postoperative survival time, hepatocyte regeneration, liver function, serum inflammatory cytokines,P-JAK2 protein,STAT3 protein and RNA were analyzed by immunohistochemistry, ELISA, or Western blot.ResultsThe high dose group demonstrated prolonged survival time (21.2±4.6h), significantly longer than both the control (9.1±2.1 h) and the low-dose group (10.6±2.3 h) (P= 0.023); as well as improved liver function with lower ALT, AST, TBIL, DBIL and higher PT at 6h and 12h post-surgery (both P<0.05). No significant differences in hepatocyte regeneration were found. Compared to the control group, the high-dose group showed significantly increases of serum inflammatory cytokines IL-1 and IL-10, and decrease of IL-6 (P<0.05). P-JAK2 protein,STAT3 protein and P-p65 protein were significant lower in the MgIG treated group than that of the control at 6h,12h and 18h after surgery (P<0.05).ConclusionHigh-dose MgIG can extend survival time in rat after excessive hepatectomy. This hepatoprotective effect was not by increase hepatocyte regeneration but rather by inhibiting the inflammatory response through inhibition of JAK2-STAT3 pathway.