Skip to main content
SpringerLink
Log in

Hepatoprotective Effect of Ulinastatin in a Rat Model of Major Hepatectomy After Obstructive Jaundice

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

To date, major hepatectomy with obstructive jaundice is still a highly risky and difficult surgery because of the high rate of complications. An excessive inflammatory response may be the primary hindrance to postoperative recovery of liver function.

Aims

Recent research has demonstrated that ulinastatin blocks the release of inflammatory factors and prevents the cytokine cascade reaction. This study was conducted to investigate the effect of ulinastatin on major hepatectomy after obstructive jaundice and to explore the potential mechanisms of this effect.

Methods

Male Sprague–Dawley rats were divided into three groups: sham, control and treated groups. In the control and treated groups, obstructive jaundice was induced, and a 70 % major hepatectomy was performed with implementation of ulinastatin treatment in the treated group but not the control group. The rats were sacrificed after hepatectomy on day 1, day 3, day 5 and day 7. The survival time, liver function, inflammatory cytokine expression and the indices of proliferation activities were examined. Kupffer cells were isolated, and the mRNA and protein levels of CD14 and NF-κB P65 in the Kupffer cells were determined.

Results

Compared to the control group, the survival rates, postoperative liver function, and the indices of proliferation activities were better in the treated group; in the treated group serum TNF-α and IL-6 levels were lower whereas serum IL-10 levels were higher. The expression of CD14 and NF-κB P65 in Kupffer cells at both the mRNA and protein levels was significantly higher in the control group than in the treated group.

Conclusions

Ulinastatin has a protective effect in major hepatectomy with obstructive jaundice by inhibiting Kupffer cell activation and modulating the hepatic cytokine response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg. 2000;232:166–174.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Kondo S, Takada T, Miyazaki M, et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepato-Biliary-Pancreat Surg. 2008;15:41–54.

    Article  Google Scholar 

  3. Benzoni E, Molaro R, Cedolini C, et al. Liver resection for HCC: analysis of causes and risk factors linked to postoperative complications. Hepatogastroenterology. 2007;54:186–189.

    PubMed  Google Scholar 

  4. Jin S, Fu Q, Wuyun G, Wuyun T. Management of post-hepatectomy complications. World J Gastroenterol. 2013;19:7983–7991.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Deitch EA, Sittig K, Li M, Berg R, Specian RD. Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg. 1990;159:79–84.

    Article  CAS  PubMed  Google Scholar 

  6. Sheen-Chen SM, Ho HT, Chia-Pei L, Hung KS, Eng HL. The effect of insulin-like growth factor-I on hepatocyte apoptosis after bile duct ligation in rat. Dig Dis Sci. 2006;51:2220–2224.

    Article  CAS  PubMed  Google Scholar 

  7. Pulitano C, Crawford M, Joseph D, Aldrighetti L, Sandroussi C. Preoperative assessment of postoperative liver function: the importance of residual liver volume. J Surg Oncol. 2014;110:445–450.

    Article  PubMed  Google Scholar 

  8. Liu F, Li Y, Wei Y, Li B. Preoperative biliary drainage before resection for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis Sci. 2011;56:663–672.

    Article  PubMed  Google Scholar 

  9. Rerknimitr R, Angsuwatcharakon P, Ratanachu-ek T, et al. Asia-Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma. J Gastroenterol Hepatol. 2013;28:593–607.

    Article  PubMed  Google Scholar 

  10. Makino H, Shimizu H, Ito H, et al. Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy. World J Gastroenterol. 2006;12:2053–2059.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Fujiwara Y, Shimada M, Yamashita Y, et al. Cytokine characteristics of jaundice in mouse liver. Cytokine. 2001;13:188–191.

    Article  CAS  PubMed  Google Scholar 

  12. Badger SA, Jones C, McCaigue M, et al. Cytokine response to portal endotoxaemia and neutrophil stimulation in obstructive jaundice. Eur J Gastroenterol Hepatol. 2012;24:25–32.

    Article  CAS  PubMed  Google Scholar 

  13. Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89:1269–1339.

    Article  CAS  PubMed  Google Scholar 

  14. Yang YL, Li JP, Xu XP, Dou KF, Yue SQ, Li KZ. Protective effects of tumor necrosis factor alpha antibody and ulinastatin on liver ischemic reperfusion in rats. World J Gastroenterol. 2004;10:3161–3164.

    CAS  PubMed  Google Scholar 

  15. Lu J, Chen YP, Wan R, Guo CY, Wang XP. Protective effects of ulinastatin on acute liver failure induced by lipopolysaccharide/d-galactosamine. Dig Dis Sci. 2012;57:399–404.

    Article  CAS  PubMed  Google Scholar 

  16. Higgins GM, Anderson RM. Experimental pathology of the liver: restoration of the liver on the white rat following partial surgical removal. Arch Pathol. 1931.

  17. dos Santos JS, Kemp R, de Andrade MF, Neder L. Influence of biliary anastomosis on recovery from secondary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2012;24:1039–1050.

    Article  PubMed  Google Scholar 

  18. Gong JP, Wu CX, Liu CA, et al. Intestinal damage mediated by Kupffer cells in rats with endotoxemia. World J Gastroenterol. 2002;8:923–927.

    CAS  PubMed  Google Scholar 

  19. Dawiskiba J, Kornafel P, Kwiatkowska D, Zimecki M. Alterations of tumor necrosis factor-alpha and interleukin 6 production and activity of the reticuloendothelial system in experimental obstructive jaundice in rats. HPB. 2002;4:11–19.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Diamond T, Dolan S, Thompson RL, Rowlands BJ. Development and reversal of endotoxemia and endotoxin-related death in obstructive jaundice. Surgery. 1990;108:370–374.; discussion 374–375.

    CAS  PubMed  Google Scholar 

  21. Maraslioglu M, Oppermann E, Blattner C, et al. Chronic ethanol feeding modulates inflammatory mediators, activation of nuclear factor-kappaB, and responsiveness to endotoxin in murine Kupffer cells and circulating leukocytes. Mediators Inflamm. 2014;2014:808695.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Onder A, Kapan M, Yuksel H, et al. The effects of erythropoietin on bacterial translocation and inflammation in rats with obstructive jaundice. Ann Ital Chir. 2014;85:159–165.

    PubMed  Google Scholar 

  23. Yang LQ, Song JC, Irwin MG, Song JG, Sun YM, Yu WF. A clinical prospective comparison of anesthetics sensitivity and hemodynamic effect among patients with or without obstructive jaundice. Acta Anaesthesiol Scand. 2010;54:871–877.

    Article  CAS  PubMed  Google Scholar 

  24. Pergel A, Zengin K, Cercel A, Aki H, Kaya S. The effects of somatostatin and ursodeoxycholic acid in preventing the ischemic injury of the liver following Pringle maneuver in obstructive jaundice-rat model. Hepatogastroenterology. 2007;54:229–233.

    CAS  PubMed  Google Scholar 

  25. Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev. 2000;174:21–34.

    Article  CAS  PubMed  Google Scholar 

  26. Varfolomeev EE, Ashkenazi A. Tumor necrosis factor: an apoptosis JuNKie? Cell. 2004;116:491–497.

    Article  CAS  PubMed  Google Scholar 

  27. Muratori L, Longhi MS. The interplay between regulatory and effector T cells in autoimmune hepatitis: implications for innovative treatment strategies. J Autoimmun. 2013;46:74–80.

    Article  CAS  PubMed  Google Scholar 

  28. Mesquida M, Leszczynska A, Llorenc V, Adan A. Interleukin-6 blockade in ocular inflammatory diseases. Clin Exp Immunol. 2014;176:301–309.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Zhang LJ, Wang XZ. Interleukin-10 and chronic liver disease. World J Gastroenterol. 2006;12:1681–1685.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Yoshidome H, Kato A, Edwards MJ, Lentsch AB. Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice: implications of a central role for nuclear factor kappaB. Hepatology (Baltimore, MD). 1999;30:203–208.

    Article  CAS  Google Scholar 

  31. Smith K. Liver disease: Kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:503.

    Article  PubMed  Google Scholar 

  32. Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. Kupffer cells in the liver. Compr Physiol. 2013;3:785–797.

    PubMed  Google Scholar 

  33. Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci. 2007;96:2–15.

    Article  CAS  PubMed  Google Scholar 

  34. Okaya T, Lentsch AB. Cytokine cascades and the hepatic inflammatory response to ischemia and reperfusion. J Invest Surg. 2003;16:141–147.

    Article  PubMed  Google Scholar 

  35. Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 2006;12:7413–7420.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology (Baltimore, MD). 2003;37:1043–1055.

    Article  CAS  Google Scholar 

  37. Mustafa SB, Flickinger BD, Olson MS. Suppression of lipopolysaccharide-induced nitric oxide synthase expression by platelet-activating factor receptor antagonists in the rat liver and cultured rat Kupffer cells. Hepatology (Baltimore, MD). 1999;30:1206–1214.

    Article  CAS  Google Scholar 

  38. Hsieh WT, Liu YT, Lin WC. Anti-inflammatory properties of Ajuga bracteosa in vivo and in vitro study and their effects on mouse model of liver fibrosis. J Ethnopharmacol. 2011;135:116–125.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Science and Technology Planning Project of Guangdong Province (No. 2012B061700105), China.

Conflict of interest

None.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biliary-Pancreatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China

      Xun Li, Yang-Jie Ou, Xiao-Xu Zhu, Xiao-Yu Yin & Di Tang

    2. Department of Cadre Ward, The 181st Hospital of Chinese People’s Liberation Army, Guilin, 541002, China

      Jing Li

    3. Department of Ultrasonography, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China

      Yun-Xiao Zhu

    Authors
    1. Xun Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jing Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yang-Jie Ou
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiao-Xu Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiao-Yu Yin
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yun-Xiao Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Di Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Yun-Xiao Zhu or Di Tang.

    Additional information

    Xun Li and Jing Li have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Li, X., Li, J., Ou, YJ. et al. Hepatoprotective Effect of Ulinastatin in a Rat Model of Major Hepatectomy After Obstructive Jaundice. Dig Dis Sci 60, 1680–1689 (2015). https://doi.org/10.1007/s10620-015-3543-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10620-015-3543-x

    Keywords

    Search

    Navigation