The Clinical Study On The Effects Of Inflammatory Cytokines And Ulinastatin On Inflammatoroy Cytokines In Patients Undergoing Partial Hepatectomy

Chapterl. Various inflammatory cytokines to partial hepatectomy in patients with a healthy or a diseased liverHepatocellular carcinoma (HCC) is one of the deadliest cancers throughout the world. With the highest hepatitis B virus infection rate, the incidence of HCC in China accounts for almost half of the total cases in the world. Accurate statistics on cancer occurrence and outcome are essential, both for the purposes of research and for the planning and evaluation of programs for cancer control. For the last30years, the International Agency for Research on Cancer (IARC) has published regular estimates of the incidence of, and mortality from cancer worldwide in broad areas of the world. The most recent set of estimates for2002have now been updated to2008using new sources of data and improved methods of estimation. Estimates of the worldwide incidence and mortality from27cancers in2008have been prepared for182countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. An estimated12.7million new cancer cases and7.6million cancer deaths occur in2008, with56%of new cancer cases and63%of the cancer deaths occurring in the less developed regions of the world. The most common causes of cancer death are lung cancer (1.38million,18.2%of the total), stomach cancer (738,000deaths,9.7%) and liver cancer(696,000deaths,9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Recent investigations have reviewed the survival of early tumors properly selected to receive radical therapies and the natural outcome of nonsurgical HCC patients. These data enable a new staging system to be proposed, the Barcelona Clinic Liver Cancer (BCLC) staging classification, that comprises four stages that select the best candidates for the best therapies currently available. Early stage (A) includes patients with asymptomatic early tumors suitable for radical therapies resection, transplantation or percutaneous treatments. Intermediate stage (B) comprises patients with asymptomatic multinodular HCC. Advanced stage (C) includes patients with symptomatic tumors and/or an invasive tumoral pattern (vascular invasion/extrahepatic spread). Stage B and C patients may receive palliative treatments/new agents in the setting of phase Ⅱ investigations or randomized controlled trials. End-stage disease (D) contain patients with extremely grim prognosis that should merely receive symptomatic treatment. Liver surgery has grown over2000years from the mystic hepatoscopy of the Babylonians to the ultimate of orthotopic transplantation by Starzl in1968. The first successful liver resection was for trauma by Hildanus in the17th century. The first successful planned resection was by Langenbuch in1888and the first hemihepatectomy by Wendel in1911. Starzl brought liver transplantation to its current status and Bismuth introduced hepatobiliary units as a means of optimizing treatment of liver disease. Now, Living related donor liver transplantation (LRLT) is a new form of therapy for patients with end-stage liver disease that is being used to overcome the problem of organ donor shortage. The major medical and ethical concern of this technique is the risk to the donor. This concern is legitimate, as hepatectomy is major upper abdominal surgery, and the liver plays a major role in maintaining host-defense homeostasis. Donor hepatectomy with maximal safety is a principal concern during living donor liver transplantation. Recently, because of insufficient surveillance systems for the population at risk in China, HCC is frequently found in later stages, liver resection could be life threatening, with fulminant liver failure postoperatively, which is related to an overwhelming inflammatory response in the residual liver. The reported mortality and morbidity rates associated with hepatectomy are mostly high in patients with liver disease.Surgical stress induces complex modifications in the hemodynamic, metabolic, neuro-hormonal and immune response of the individual. The magnitude of these alterations depends on preoperative events leading to surgery, the severity of surgical trauma, and also on post-operative complications. Surgery trauma is followed by an immune-inflammatory response, initiated at the site of injury by the innate immune system, followed by a compensatory anti-inflammatory response (CARS), involving mainly cells of the adaptive immune system, which predispose the host to septic complications. We all know that partial hepatectomy is a major upper abdominal operation associated with certain stress to the patient. Successful adaptation to such stress is a prerequisite for survival.ObjectiveThe purpose of the study was to compare the inflammatory response by assessing cytokines induced by hepatectomy in patients with a healthy liver and those with a diseased liver.Materials and methodsTwelve patients undergoing partial right hepatectomy were enrolled in this study. Six of them were donors for living related liver transplantation (group A, GA); the other six were patients with hepatocellular carcinoma (group B, GB). Blood samples for interleukin-6(IL-6), interleukin-8(IL-8), interleukin-10(IL-10), tumor necrosis factor-α (TNF-α)-assays were collected before the operation, at the end of the operation, and6and24hours after the operation. All values are expressed as mean±SD. The data were analyzed and compared in each group using Student’s t tests. Repeated-measures analysis of variance of general linear models was used to compare trends of changes in different variables.ResultsRepeated-measures analysis of variance was used to compare the trends of changes in inflammatory mediators. There were significant difference between group A and group B in IL-6, IL-10and IL-8at24h after the operation(P<0.05). There were no differences in all cytokines values between the two groups before operation. Also, there was no difference between the2groups in TNF-a. Changes in IL-6in the2groups are shown that IL-6levers at the end of the operation and24h after the operation in group B increased significantly than group A, and also the levels of the IL-8at24h after the operation. However, changes in IL-10are opposite. Significantly higher levels of IL-10at the end of the operation and6h after the operation in group A than group B.ConclusionResults showed that resection of the liver in patients with both healthy and diseased livers leads to significant increases in IL-6, IL-8and IL-10. Significantly lower levels of IL-6at the end of the operation and6h after the operation, and also lower levels of IL-8at24h after the operation but higher levels of IL-10at the end of the operation and6h after the operation in GA patients compared to those in GB suggests that GA patients adapted to surgical inflammatory response more easily than did the GB patients.Chapter2. The clinic study on the effects of ulinastatin on various inflammatory cytokines in patients undergoing resection of hepatocellular carcinomaLiver resection remains the primary treatment for liver lesions, including liver malignancies, and massive hepatectomy is also widely performed for those with large liver lesions in areas where lesions are not usually found in their earlier stages. The failure of liver function following surgery has thus been one of the major issues attracting the attention of many hepatobiliary surgeons. The damage to residual hepatocytes caused by the inflammatory response following liver resection may be much more significant and influential than formerly thought. However, to the best of our knowledge, there are few clinical reports concerning anti-inflammatory treatment using any clinically available medications following hepatectomy in the clinic, even though hundreds of liver resections are performed at every major medical center in China each year. Inflammatory damage in the residual liver at an earlier stage following hepatectomy might play an important role in the failure of surgical recovery. The application of proper anti-inflammatory agents might improve surgical outcomes in major liver resection, so we should take measures to manipulate this inflammation to protect residual liver function, achieve better recovery, and improve survival in clinical studies.Ulinastatin (UTI) is one of the Kunitz-type protease inhibitors found in urine. Various serine proteases such as trypsin, chymotrypsin, neutrophil elastase and plasmin are inhibited by UTI. It has previously been used in the clinic in patients with acute pancreatitis and patients following pancreatic surgery, with reasonably satisfactory effects. UTI has also been indicated to have an ability to block the excessive inflammatory response via a mechanism of reducing biolipid membrane fluidity and interfering with receptors and ligands. Moreover, UTI may prevent macrophages from releasing proinflammatory cytokines.ObjectiveThis study is a prospective, randomized, double-blind study designed to investigate the effects of ulinastatin on inflammatory responses in patients under going partial hepatectomy.Materials and methodsThe protocol of this study was approved by the ethics committee of Southern Hospital. Written informed consent was obtained from each patient. Forty patients admitted to the hospital for partial hepatectomy were equally randomized into two groups:the UTI group and the control group, receiving ulinastatin10,000U.kg-1and saline vehicle respectively in the beginning20min of surgery. The venous blood samples were taken from the internal jugular vein before the operation(T1), after the operation(T2),6h(T3) and24h(T4) after the operation. Interleukin-6(IL-6), interleukin-8(IL-8), interleukin-10(IL-10) and tumor necrosis factor (TNF)-α were measured. All values are expressed as mean±SD. The data were analyzed and compared in each group using Student’s t tests. Repeated-measures analysis of variance of general linear models was used to compare trends of changes in different variables.ResultsRepeated-measures analysis of variance was used to compare the trends of changes in inflammatory mediators. There were no differences in all cytokines values between the two groups before operation. There were significant difference between the2groups(P<.01). IL-6, IL-8and IL-10levels increased over time in both groups, and moreover IL-6, IL-10levels in serum at all time points increased significantly as compared with those in samples collected at before operation (P<0.05). Compared with the control group, the UTI treatment groups showed significantly lower levels of IL-6(P<0.05), also significantly up-regulated was the expression of IL-10in group UTI (P<0.01).ConclusionThe protective role of UTI in patients undergoing partial hepatectomy possibly via down-regulating the expression of pro-inflammatory cytokines in serum, while promoting the production of anti-inflammatory factors. These results suggest that perioperative administration of UTI might deserve further assessment for use in modulating acute phase responses in patients undergoing hepatic resection.