BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Co-administration of erythropoietin and iron complex improves late-phase liver regeneration

  • Kim, Ji-Yoon (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Choi, Dongho (Department of Surgery, Hanyang University Hospital) ;
  • Kim, Joohwan (Department of Molecular and Cellular Biochemistry, Kangwon National University, School of Medicine) ;
  • Kim, Young-Myeong (Department of Molecular and Cellular Biochemistry, Kangwon National University, School of Medicine) ;
  • Lim, Hyunyoung (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Sung, Jeong Min (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Lee, Min Kyu (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Choung, Yoo Jin (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Chang, Ji Hee (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Jeong, Mi Ae (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital)
  • Received : 2019.06.12
  • Accepted : 2019.07.23
  • Published : 2020.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Erythropoietin and iron have individually shown beneficial effects on early-phase liver regeneration following partial hepatectomy (PHx); however, there are limited data on the combined effect on late-phase liver regeneration after PHx. Here we examined combined effects of recombinant human erythropoietin (rhEPO, 3,000 IU/kg) and iron isomaltoside (IIM, 40 mg/kg) on late-phase liver regeneration following PHx and investigated the possible underlying mechanism. Rats administrated with rhEPO showed significantly higher liver mass restoration, interleukin-6 (IL-6, a hepatocyte mitogen) levels, and Ki-67-positive hepatocytes on day 7 after PHx than saline-treated controls. These beneficial effects were further enhanced on days 7 and 14 by co-treatment with IIM. This combination also significantly improved liver function indices, such as increased albumin production and decreased bilirubin levels, but did not alter serum levels of toxic parameters, such as aspartate transaminase and alanine transaminase. This study demonstrates that the combination of rhEPO and IIM synergistically improves late-phase liver regeneration and function after PHx, probably by promoting IL-6-mediated hepatocyte proliferation without adverse effects. Thus, this combination treatment can be a potential therapeutic strategy for patients undergoing resection for hepatic malignancies.

Keywords

References

  1. Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A and Farges O (2000) Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 191, 38-46 https://doi.org/10.1016/S1072-7515(00)00261-1
  2. Garcea G and Maddern GJ (2009) Liver failure after major hepatic resection. J Hepatobiliary Pancreat Surg 16, 145-155 https://doi.org/10.1007/s00534-008-0017-y
  3. Schmeding M, Boas-Knoop S, Lippert S et al (2008) Erythropoietin promotes hepatic regeneration after extended liver resection in rats. J Gastroenterol Hepatol 23, 1125-1131 https://doi.org/10.1111/j.1440-1746.2007.05265.x
  4. Greif F, Ben-Ari Z, Taya R et al (2010) Dual effect of erythropoietin on liver protection and regeneration after subtotal hepatectomy in rats. Liver Transpl 16, 631-638 https://doi.org/10.1002/lt.22046
  5. Bockhorn M, Fingas CD, Rauen U et al (2008) Erythropoietin treatment improves liver regeneration and survival in rat models of extended liver resection and living donor liver transplantation. Transplantation 86, 1578-1585 https://doi.org/10.1097/TP.0b013e31818b22b4
  6. An S, Soe K, Akamatsu M, Hishikawa Y and Koji T (2012) Accelerated proliferation of hepatocytes in rats with iron overload after partial hepatectomy. Histochem Cell Biol 138, 773-786 https://doi.org/10.1007/s00418-012-0994-4
  7. Seehofer D, Neumann UP, Schirmeier A et al (2008) Synergistic effect of erythropoietin but not G-CSF in combination with curcumin on impaired liver regeneration in rats. Langenbecks Arch Surg 393, 325-332 https://doi.org/10.1007/s00423-008-0290-x
  8. Michalopoulos GK and DeFrances MC (1997) Liver regeneration. Science 276, 60-66 https://doi.org/10.1126/science.276.5309.60
  9. Tao Y, Wang M, Chen E and Tang H (2017) Liver regeneration: Analysis of the main relevant signaling molecules. Mediators Inflamm 2017, 4256352
  10. Jelkmann W (2004) Molecular biology of erythropoietin. Intern Med 43,649-659. https://doi.org/10.2169/internalmedicine.43.649
  11. Ghezzi P and Brines M (2004) Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 11, S37-44 https://doi.org/10.1038/sj.cdd.4401450
  12. Fan H, Villegas C and Wright JA (1996) A link between ferritin gene expression and ribonucleotide reductase R2 protein, as demonstrated by retroviral vector mediated stable expression of R2 cDNA. FEBS Lett 382, 145-148 https://doi.org/10.1016/0014-5793(96)00143-3
  13. Kuma S, Inaba M, Ogata H et al (1990) Effect of human recombinant interleukin-6 on the proliferation of mouse hepatocytes in the primary culture. Immunobiology 180, 235-242 https://doi.org/10.1016/S0171-2985(11)80331-1
  14. Kang LI, Mars WM, and Michalopoulos GK (2012) Signals and cells involved in regulating liver regeneration. Cells 1, 1261-1292 https://doi.org/10.3390/cells1041261
  15. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA and Thorgeirsson SS (2004) Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A 101, 4477-4482 https://doi.org/10.1073/pnas.0306068101
  16. Yokoyama Y, Nagino M and Nimura Y (2007) Mechanisms of hepatic regeneration following portal vein embolization and partial hepatectomy: a review. World J Surg 31, 367-374 https://doi.org/10.1007/s00268-006-0526-2
  17. Fisette A, Hassanain M, Metrakos P et al (2012) High-dose insulin therapy reduces postoperative liver dysfunction and complications in liver resection patients through reduced apoptosis and altered inflammation. J Clin Endocrinol Metab 97, 217-226 https://doi.org/10.1210/jc.2011-1598
  18. Pawlik TM, Poon RT, Abdalla EK et al (2005) Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma. Arch Surg 140, 450-457 https://doi.org/10.1001/archsurg.140.5.450
  19. Mollbrink A, Holmstrom P, Sjostrom M, Hultcrantz R, Eriksson LC and Stal P (2012) Iron-regulatory gene expression during liver regeneration. Scand J Gastroenterol 47, 591-600 https://doi.org/10.3109/00365521.2012.661761
  20. Pachowka M, Zegarska J, Ciecierski R and Korczak-Kowalska G (2008) The role of IL-6 during the late phase of liver regeneration. Ann Transplant 13, 15-19
  21. Cui Y, Konig J, Leier I, Buchholz U and Keppler D (2001) Hepaticuptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 276, 9626-9630 https://doi.org/10.1074/jbc.M004968200
  22. Lehmann K, Tschuor C, Rickenbacher A et al (2012) Liver failure after extended hepatectomy in mice is mediated by a p21-dependent barrier to liver regeneration. Gastroenterology 143, 1609-1619 https://doi.org/10.1053/j.gastro.2012.08.043
  23. Koniaris LG, McKillop IA and Schwartz SI (2003) Liver regeneration. J Am Coll Surg 197, 634-659 https://doi.org/10.1016/S1072-7515(03)00374-0
  24. Balleari E, Clavio M, Arboscello E et al (2011) Weekly standard doses of rh-EPO are highly effective for the treatment of anemic patients with low-intermediate 1 risk myelodysplastic syndromes. Leuk Res 35, 1472-1476 https://doi.org/10.1016/j.leukres.2011.05.025
  25. Ehrenreich H, Weissenborn K, Prange H et al (2009) Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 40, e647-656 https://doi.org/10.1161/STROKEAHA.109.564872
  26. Danielson J (2004) Structure, chemistry, and pharmacokinetics of intravenous iron agents. Am Soc Nephrol 15, S93-98
  27. Wikstrom B, Bhandari S, Barany P et al (2011) Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease. J Nephrol 24, 589-596 https://doi.org/10.5301/JN.2011.6248
  28. Kalra PA and Bhandari S (2016) Efficacy and safety of iron isomaltoside (Monofer((R)) in the management of patients with iron deficiency anemia. Int J Nephrol Renovasc Dis 9, 53-64 https://doi.org/10.2147/IJNRD.S89704
  29. Higgins GM and Anderson RM (1931) Experimental pathology of the liver. 1. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol 12, 186-202
  30. Meier M, Andersen KJ, Knudsen AR, Nyengaard JR, Hamilton-Dutoit S and Mortensen FV (2016) Liver regeneration is dependent on the extent of hepatectomy. J Surg Res 205, 76-84 https://doi.org/10.1016/j.jss.2016.06.020