Combined kidney‑liver perfusion enhances the proliferation effects of hypothermic perfusion on liver grafts
via upregulation of IL‑6/Stat3 signaling

Li,Jianhui; Jia,Junjun; He,Ning; Jiang,Li; Yu,Hao; Li,Haoyu; Peng,Yifan; Xie,Haiyang; Zhou,Lin; Zheng,Shusen

doi:10.3892/mmr.2019.10379

Combined kidney‑liver perfusion enhances the proliferation effects of hypothermic perfusion on liver grafts via upregulation of IL‑6/Stat3 signaling

Authors:
- Jianhui Li
- Junjun Jia
- Ning He
- Li Jiang
- Hao Yu
- Haoyu Li
- Yifan Peng
- Haiyang Xie
- Lin Zhou
- Shusen Zheng
View Affiliations

Affiliations: Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: June 12, 2019 https://doi.org/10.3892/mmr.2019.10379
Pages: 1663-1671
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

A limited number of studies have revealed that adding kidneys to liver perfusion may maintain an improved physiological balance; however, the underlying mechanism remains to be elucidated. The preset study confirmed the protective role of this new model and investigated the underlying mechanisms. Methods: A total of 12 rats were randomly assigned into two groups (n=6 for each group): The kidney‑liver perfusion (KL) group and liver perfusion (LP) group. Perfusate samples were collected during the perfusion process for the analysis of pH, K+ and liver function. Liver tissues were obtained for the evaluation of adenosine triphosphate (ATP), terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labelling and immunohistochemistry of Ki67. Cell cycle inhibitors, apoptosis‑associated genes and signal transducer and activator of transcription 3 (Stat3) were analyzed using quantitative polymerase chain reaction and western blot analysis. Results: Overall pH and K+ values of the KL group were significantly different from the LP group and more stable; aspartate aminotransferase, alanine transaminase and lactate dehydrogenase levels increased progressively over time in the LP group and were significantly different at different time points compared with pre‑perfusion levels and the KL group, which suggested the KL group was superior to the LP group. In addition, KL reduced portal vein resistance and was associated with lower ATP consumption compared with the LP group. Furthermore, liver proliferation was upregulated with the upregulation of the interleukin 6 (IL‑6)/Stat3 signaling pathway in KL compared with LP. The present study revealed for the first time that KL and hypothermic machine perfusion demonstrated a more proactive repair capability by maintaining liver regeneration via the upregulation of the IL‑6/Stat3 signaling pathway.

View Figures

View References

1	Schlegel A and Dutkowski P: Role of hypothermic machine perfusion in liver transplantation. Transpl Int. 28:677–689. 2015. View Article : Google Scholar : PubMed/NCBI
2	Jia JJ, Zhang J, Li JH, Chen XD, Jiang L, Zhou YF, He N, Xie HY, Zhou L and Zheng SS: Influence of perfusate on liver viability during hypothermic machine perfusion. World J Gastroenterol. 21:8848–8857. 2015. View Article : Google Scholar : PubMed/NCBI
3	Hosgood SA, Bagul A and Nicholson ML: Minimising cold ischaemic injury in an experimental model of kidney transplantation. Eur J Clin Invest. 41:233–240. 2011. View Article : Google Scholar : PubMed/NCBI
4	Newsome PN, Henderson NC, Nelson LJ, Dabos C, Filippi C, Bellamy C, Howie F, Clutton RE, King T, Lee A, et al: Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure. BMC Gastroenterol. 10:342010. View Article : Google Scholar : PubMed/NCBI
5	Wyss M and Kaddurah-Daouk R: Creatine and creatinine metabolism. Physiol Rev. 80:1107–1213. 2000. View Article : Google Scholar : PubMed/NCBI
6	Chung WY, Gravante G, Al-Leswas D, Arshad A, Sorge R, Watson CC, Pollard C, Metcalfe MS and Dennison AR: The development of a multiorgan ex vivo perfused model: Results with the porcine liver-kidney circuit over 24 h. Artif Organs. 37:457–466. 2013. View Article : Google Scholar : PubMed/NCBI
7	Chung WY, Gravante G, Al-Leswas D, Alzaraa A, Sorge R, Ong SL, Pollard C, Lloyd DM, Metcalfe MS and Dennison AR: The autologous normothermic ex vivo perfused porcine liver-kidney model: Improving the circuit's biochemical and acid-base environment. Am J Surg. 204:518–526. 2012. View Article : Google Scholar : PubMed/NCBI
8	Mahboub P, Ottens P, Seelen M, t Hart N, Van Goor H, Ploeg R, Martins PN and Leuvenink H: Gradual rewarming with gradual increase in pressure during machine perfusion after cold static preservation reduces kidney ischemia reperfusion injury. PLoS One. 10:e01438592015. View Article : Google Scholar : PubMed/NCBI
9	Kamada N and Calne RY: A surgical experience with five hundred thirty liver transplants in the rat. Surgery. 93:64–69. 1983.PubMed/NCBI
10	Lai SS, Zhao DD, Cao P, Lu K, Luo OY, Chen WB, Liu J, Jiang EZ, Yu ZH, Lee G, et al: PP2Acα positively regulates the termination of liver regeneration in mice through the AKT/GSK3β/Cyclin D1 pathway. J Hepatol. 64:352–360. 2016. View Article : Google Scholar : PubMed/NCBI
11	Huang Q, Zhan L, Cao H, Li J, Lyu Y, Guo X, Zhang J, Ji L, Ren T, An J, et al: Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 12:999–1014. 2016. View Article : Google Scholar : PubMed/NCBI
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
13	Yang X, Jiang H and Shi Y: Upregulation of heme oxygenase-1 expression by curcumin conferring protection from hydrogen peroxide-induced apoptosis in H9c2 cardiomyoblasts. Cell Biosci. 7:202017. View Article : Google Scholar : PubMed/NCBI
14	Reiling J, Lockwood DS, Simpson AH, Campbell CM, Bridle KR, Santrampurwala N, Britton LJ, Crawford DH, Dejong CH and Fawcett J: Urea production during normothermic machine perfusion: Price of success? Liver Transpl. 21:700–703. 2015. View Article : Google Scholar : PubMed/NCBI
15	Chung WY, Gravante G, Eltweri A, Sorge R, Ong SL, Pollard C, Metcalfe M and Dennison A: The ‘kidney-liver’ multiorgan ex vivo perfused model improves the circuit's biochemical milieu during perfusion compared to the ‘liver-kidney’ counterpart. J Artif Organs. 18:151–161. 2015. View Article : Google Scholar : PubMed/NCBI
16	Gravante G, Ong SL, Metcalfe MS, Sorge R, Fox AJ, Lloyd DM, Maddern GJ and Dennison AR: Changes in acid-base balance during electrolytic ablation in an ex vivo perfused liver model. Am J Surg. 204:666–670. 2012. View Article : Google Scholar : PubMed/NCBI
17	He X, Ji F, Zhang Z, Tang Y, Yang L, Huang S, Li W, Su Q, Xiong W, Zhu Z, et al: Combined liver-kidney perfusion enhances protective effects of normothermic perfusion on liver grafts from donation after cardiac death. Liver Transpl. 24:67–79. 2018. View Article : Google Scholar : PubMed/NCBI
18	Liu Q, Nassar A, Farias K, Buccini L, Baldwin W, Mangino M, Bennett A, O'Rourke C, Okamoto T, Uso TD, et al: Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers. Liver Transpl. 20:987–999. 2014. View Article : Google Scholar : PubMed/NCBI
19	Boncompagni E, Gini E, Ferrigno A, Milanesi G, Gringeri E, Barni S, Cillo U, Vairetti M and Freitas I: Decreased apoptosis in fatty livers submitted to subnormothermic machine-perfusion respect to cold storage. Eur J Histochem. 55:e402011. View Article : Google Scholar : PubMed/NCBI
20	Guan JJ, Zhang XD, Sun W, Qi L, Wu JC and Qin ZH: DRAM1 regulates apoptosis through increasing protein levels and lysosomal localization of BAX. Cell Death Dis. 6:e16242015. View Article : Google Scholar : PubMed/NCBI
21	Chen H, Zhang J, Gao Y, Liu S, Koh K, Zhu X and Yin Y: Sensitive cell apoptosis assay based on caspase-3 activity detection with graphene oxide-assisted electrochemical signal amplification. Biosens Bioelectron. 68:777–782. 2015. View Article : Google Scholar : PubMed/NCBI
22	López-Luque J, Caballero-Diaz D, Martinez-Palacián A, Roncero C, Moreno-Càceres J, García-Bravo M, Grueso E, Fernández A, Crosas-Molist E, García-Álvaro M, et al: Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis. Hepatology. 63:604–619. 2016. View Article : Google Scholar : PubMed/NCBI
23	Lai SS, Zhao DD, Cao P, Lu K, Luo OY, Chen WB, Liu J, Jiang EZ, Yu ZH, Lee G, et al: PP2Acα positively regulates the termination of liver regeneration in mice through the AKT/GSK3β/Cyclin D1 pathway. J Hepatol. 64:352–360. 2016. View Article : Google Scholar : PubMed/NCBI
24	Liu Y, Shao M, Wu Y, Yan C, Jiang S, Liu J, Dai J, Yang L, Li J, Jia W, et al: Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses. J Hepatol. 62:590–598. 2015. View Article : Google Scholar : PubMed/NCBI