Skip to main content
SpringerLink
Log in

Sufentanil Protects the Liver from Ischemia/Reperfusion-Induced Inflammation and Apoptosis by Inhibiting ATF4-Induced TP53BP2 Expression

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. This study aimed to investigate the protective effect and potential mechanisms of sufentanil on hepatic I/R injury. I/R rat model and hypoxic/reoxygenation (H/R)-induced buffalo rat liver (BRL)-3A cell model were established. Following pretreatment with sufentanil, the enzymatic activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rat serum and the changes of hepatic histopathology were evaluated to track the extent of liver injury. The levels of inflammatory factors were determined with ELISA kits and RT-qPCR. The infiltration of macrophages was assessed after detecting monocyte chemoattractant protein 1 (MCP-1) and F4/80 expression. Additionally, apoptosis was measured by means of TUNEL staining, and gene expression related to apoptosis was examined using RT-qPCR and western blotting. Then, TP53BP2 was overexpressed in BRL-3A cells exposed to H/R condition to evaluate whether sufentanil defended the liver against injury by regulating TP53BP2 expression. Moreover, the potential binding site of ATF4 on the TP53BP2 promoter was analyzed using JASPAR databases and verified by chromosomal immunoprecipitation (ChIP) assay. Furthermore, TP53BP2 expression and endoplasmic reticulum stress (ERS)-related protein levels were determined after ATF4 was overexpressed in sufentanil-treated BRL-3A cells. Results revealed that sufentanil significantly improved hepatic I/R injury, decreased the levels of inflammatory factors, and alleviated hepatocyte apoptosis. Notably, upregulated TP53BP2 expression was observed in hepatic tissues, and TP53BP2 overexpression markedly reversed the protective effects of sufentanil on the inflammation and apoptosis in H/R-stimulated BRL-3A cells. Additionally, ATF4 was confirmed to combine with the TP53BP2 promoter. ATF4 upregulation attenuated the inhibitory effects of sufentanil on the expression of TP53BP2 and ERS-associated proteins. These findings demonstrated that sufentanil protects the liver from inflammation and apoptosis injury induced by I/R by inhibiting ATF4 expression and further suppressing TP53BP2 expression, suggesting a promising therapeutic candidate for the treatment of liver I/R injury.

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
Fig. 7

Similar content being viewed by others

Data Availability

The datasets used and/or analyzed during this study were accessed via the corresponding authors on reasonable request.

References

  1. Ajamieh, H., G.C. Farrell, R.S. McCuskey, J. Yu, E. Chu, H.J. Wong, W. Lam, and N.C. Teoh. 2015. Acute atorvastatin is hepatoprotective against ischaemia-reperfusion injury in mice by modulating eNOS and microparticle formation. Liver International 35 (9): 2174–2186. https://doi.org/10.1111/liv.12827.

    Article  CAS  PubMed  Google Scholar 

  2. Bergamaschi, D., Y. Samuels, B. Jin, S. Duraisingham, T. Crook, and X. Lu. 2004. ASPP1 and ASPP2: common activators of p53 family members. Molecular and Cellular Biology 24 (3): 1341–1350. https://doi.org/10.1128/mcb.24.3.1341-1350.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bergamaschi, D., Y. Samuels, A. Sullivan, M. Zvelebil, H. Breyssens, A. Bisso, G. Del Sal, et al. 2006. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nature Genetics 38 (10): 1133–1141. https://doi.org/10.1038/ng1879.

    Article  CAS  PubMed  Google Scholar 

  4. Brenner, C., L. Galluzzi, O. Kepp, and G. Kroemer. 2013. Decoding cell death signals in liver inflammation. Journal of Hepatology 59 (3): 583–594. https://doi.org/10.1016/j.jhep.2013.03.033.

    Article  CAS  PubMed  Google Scholar 

  5. Cairo, G., L. Bardella, L. Schiaffonati, and A. Bernelli-Zazzera. 1985. Synthesis of heat shock proteins in rat liver after ischemia and hyperthermia. Hepatology 5 (3): 357–361. https://doi.org/10.1002/hep.1840050303.

    Article  CAS  PubMed  Google Scholar 

  6. Chi, X.B., Y. Jiang, Y.B. Chen, F. Yang, Q.C. Cai, F. Pan, L.Z. Lv, and X.J. Zhang. 2019. Suppression of microRNA-27a protects against liver ischemia/reperfusion injury by targeting PPAR gamma and inhibiting endoplasmic reticulum stress. Molecular Medicine Reports 20 (5): 4003–4012. https://doi.org/10.3892/mmr.2019.10645.

    Article  CAS  PubMed  Google Scholar 

  7. Guo, Q.Y., H.X. Li, J.L. Liu, L. Xu, L. Yang, Z.M. Sun, and B. Zhou. 2017. Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in amurine model of neutrophilic asthma. Journal of Asthma 54 (2): 125–133. https://doi.org/10.1080/02770903.2016.1205085.

    Article  CAS  Google Scholar 

  8. Hu, Q., Q. Wang, C.G. Han, and Y. Yang. 2020. Sufentanil attenuates inflammation and oxidative stress in sepsis-induced acute lung injury by downregulating KNG1 expression. Molecular Medicine Reports 22 (5): 4298–4306. https://doi.org/10.3892/mmr.2020.11526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jaeschke, H., and B.L. Woolbright. 2012. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplantation Reviews (Orlando, Fla.) 26 (2): 103–114. https://doi.org/10.1016/j.trre.2011.10.006.

    Article  Google Scholar 

  10. Jiang, P., Z.W. Zou, R.S. Tu, S. Wang, and H.F. Yun. 2020. Sufentanil attenuates inflammation and oxidative stress in myocardial ischemia reperfusion injury via upregulating Sestrin 2 expression and activating AMPK signalling pathway. Biotechnology & Biotechnological Equipment 34 (1): 203–210. https://doi.org/10.1080/13102818.2020.1728197.

    Article  CAS  Google Scholar 

  11. Kalogeris, T., C.P. Baines, M. Krenz, and R.J. Korthuis. 2012. Cell biology of ischemia/reperfusion injury. International Review of Cell and Molecular Biology 298: 229–317. https://doi.org/10.1016/B978-0-12-394309-5.00006-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kang, J.W., and S.M. Lee. 2016. Resolvin D1 protects the liver from ischemia/reperfusion injury by enhancing M2 macrophage polarization and efferocytosis. Biochimica et Biophysica Acta 1861 (9 Pt A): 1025–1035. https://doi.org/10.1016/j.bbalip.2016.06.002.

    Article  CAS  PubMed  Google Scholar 

  13. Karaman, A., E. Fadillioglu, E. Turkmen, E. Tas, and Z. Yilmaz. 2006. Protective effects of leflunomide against ischemia-reperfusion injury of the rat liver. Pediatric Surgery International 22 (5): 428–434. https://doi.org/10.1007/s00383-006-1668-x.

    Article  PubMed  Google Scholar 

  14. Kou, X.N., J. Zhu, X.K. Xie, M.X. Hao, and Y.R. Zhao. 2020. The protective effect of glycyrrhizin on hepatic ischemia-reperfusion injury in rats and possible related signal pathway. Iranian Journal of Basic Medical Sciences 23 (9): 1232–1238. https://doi.org/10.22038/ijbms.2020.44101.10334.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li, H., G. Bai, Y.S. Ge, Q.Z. Zhang, X.D. Kong, W.J. Meng, and H.B. Wang. 2018. Hydrogen-rich saline protects against small-scale liver ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress. Life Sciences 194: 7–14. https://doi.org/10.1016/j.lfs.2017.12.022.

    Article  CAS  PubMed  Google Scholar 

  16. Li, L.S., Y. Sun, N. Zhang, X.M. Qiu, L. Wang, and Q.Y. Luo. 2019. By regulating miR-182-5p/BCL10/CYCS, sufentanil reduces the apoptosis of umbilical cord mesenchymal stem cells caused by ropivacaine. Bioscience Trends 13 (1): 49–57. https://doi.org/10.5582/bst.2018.01291.

    Article  CAS  PubMed  Google Scholar 

  17. Lian, Y.H., J. Fang, H.D. Zhou, H.F. Jiang, and K.J. Xie. 2019. Sufentanil preconditioning protects against hepatic ischemia-reperfusion injury by suppressing inflammation. Medical Science Monitor 25: 2265–2273. https://doi.org/10.12659/MSM.913145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu, K., Y. Shi, X. Guo, S. Wang, Y. Ouyang, M. Hao, D. Liu, L. Qiao, N. Li, J. Zheng, and D. Chen. 2014. CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2. Cell Death & Disease 5: e1323. https://doi.org/10.1038/cddis.2014.276.

    Article  CAS  Google Scholar 

  19. Liu, Y. 2020. Hydrogen peroxide induces nucleus pulposus cell apoptosis by ATF4/CHOP signaling pathway. Experimental and Therapeutic Medicine 20 (4): 3244–3252. https://doi.org/10.3892/etm.2020.9052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Livak, K.J., and T.D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25 (4): 402–408. https://doi.org/10.1006/meth.2001.1262.

    Article  CAS  Google Scholar 

  21. Ma, X.X., F. Luo, and N. Lan. 2019. Effects of dexmedetomidine combined with sufentanil on P2X7 receptor expression in peripheral blood mononuclear cells in patients with burn pain. Acta Microscópica 28 (4): 785–790.

    Google Scholar 

  22. Mahmoud, A.R., F.E.M. Ali, T.H. Abd-Elhamid, and E.H.M. Hassanein. 2019. Coenzyme Q10 protects hepatocytes from ischemia reperfusion-induced apoptosis and oxidative stress via regulation of Bax/Bcl-2/PUMA and Nrf-2/FOXO-3/Sirt-1 signaling pathways. Tissue & Cell 60: 1–13. https://doi.org/10.1016/j.tice.2019.07.007.

    Article  CAS  Google Scholar 

  23. Mitupatum, T., K. Aree, S. Kittisenachai, S. Roytrakul, S. Puthong, S. Kangsadalampai, and P. Rojpibulstit. 2016. mRNA expression of Bax, Bcl-2, p53, cathepsin B, caspase-3 and caspase-9 in the HepG2 cell line following induction by a novel monoclonal Ab Hep88 mAb: cross-talk for paraptosis and apoptosis. Asian Pacific Journal of Cancer Prevention 17 (2): 703–712. https://doi.org/10.7314/apjcp.2016.17.2.703.

    Article  PubMed  Google Scholar 

  24. Nasrallah, H., I. Aissa, C. Slim, M.A. Boujbiha, M.A. Zaouali, M. Bejaoui, V. Wilke, H. Ben Jannet, H. Mosbah, and H. Ben Abdennebi. 2020. Effect of oleuropein on oxidative stress, inflammation and apoptosis induced by ischemia-reperfusion injury in rat kidney. Life Sciences 255: 8. https://doi.org/10.1016/j.lfs.2020.117833.

    Article  CAS  Google Scholar 

  25. Nastos, C., K. Kalimeris, N. Papoutsidakis, M.K. Tasoulis, P.M. Lykoudis, K. Theodoraki, D. Nastou, V. Smyrniotis, and N. Arkadopoulos. 2014. Global consequences of liver ischemia/reperfusion injury. Oxidative Medicine and Cellular Longevity 2014: 906965–906913. https://doi.org/10.1155/2014/906965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rao, J.H., J.J. Qin, X.F. Qian, L. Lu, P. Wang, Z.S. Wu, Y. Zhai, F. Zhang, G.Q. Li, and X.H. Wang. 2013. Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI) through inhibiting ATF4-CHOP pathway in mice. PLoS One 8 (6): 13. https://doi.org/10.1371/journal.pone.0065568.

    Article  CAS  Google Scholar 

  27. Samuels-Lev, Y., D.J. O'Connor, D. Bergamaschi, G. Trigiante, J.K. Hsieh, S. Zhong, I. Campargue, L. Naumovski, T. Crook, and X. Lu. 2001. ASPP proteins specifically stimulate the apoptotic function of p53. Molecular Cell 8 (4): 781–794. https://doi.org/10.1016/s1097-2765(01)00367-7.

    Article  CAS  PubMed  Google Scholar 

  28. Shaker, M.E., B.N. Trawick, and W.Z. Mehal. 2016. The novel TLR9 antagonist COV08-0064 protects from ischemia/reperfusion injury in non-steatotic and steatotic mice livers. Biochemical Pharmacology 112: 90–101. https://doi.org/10.1016/j.bcp.2016.05.003.

    Article  CAS  PubMed  Google Scholar 

  29. Sun, P., P. Zhang, P.X. Wang, L.H. Zhu, Y. Du, S. Tian, X. Zhu, and H. Li. 2015. Mindin deficiency protects the liver against ischemia/reperfusion injury. Journal of Hepatology 63 (5): 1198–1211. https://doi.org/10.1016/j.jhep.2015.06.033.

    Article  CAS  PubMed  Google Scholar 

  30. Theruvath, T.P., Z. Zhong, R.T. Currin, V.K. Ramshesh, and J.J. Lemasters. 2006. Endothelial nitric oxide synthase protects transplanted mouse livers against storage/reperfusion injury: role of vasodilatory and innate immunity pathways. Transplantation Proceedings 38 (10): 3351–3357. https://doi.org/10.1016/j.transproceed.2006.10.171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vaughn, S.E. 2012. Review of the third edition of the guide for the care and use of agricultural animals in research and teaching. Journal of the American Association for Laboratory Animal Science 51 (3): 298–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Wei, Q.Q., X.F. Hu, and D. Zhang. 2020. Propofol attenuates hepatic ischemia-reperfusion injury in rats by reducing inflammation, oxidative stress and apoptosis. Latin American Journal of Pharmacy 39 (5): 1040–1046.

    CAS  Google Scholar 

  33. Wu, Q.L., T. Shen, H. Ma, and J.K. Wang. 2012. Sufentanil postconditioning protects the myocardium from ischemia-reperfusion via PI3K/Akt-GSK-3 beta pathway. Journal of Surgical Research 178 (2): 563–570. https://doi.org/10.1016/j.jss.2012.05.081.

    Article  CAS  Google Scholar 

  34. Xiao, Q., Q. Ye, W. Wang, J. Xiao, B. Fu, Z. Xia, X. Zhang, Z. Liu, and X. Zeng. 2017. Mild hypothermia pretreatment protects against liver ischemia reperfusion injury via the PI3K/AKT/FOXO3a pathway. Molecular Medicine Reports 16 (5): 7520–7526. https://doi.org/10.3892/mmr.2017.7501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xiao, Y., S.H. Zhang, Q. Li, Z.W. Liu, W.L. Mai, W. Chen, J. Lei, and H.K. Hu. 2019. miR-219a-5p ameliorates hepatic ischemia/reperfusion injury via impairing TP53BP2. Digestive Diseases and Sciences 64 (8): 2177–2186. https://doi.org/10.1007/s10620-019-05535-4.

    Article  CAS  PubMed  Google Scholar 

  36. Xin, S., and X. Ye. 2020. Oxalomalate regulates the apoptosis and insulin secretory capacity in streptozotocin-induced pancreatic beta-cells. Drug Development Research 81: 437–443. https://doi.org/10.1002/ddr.21635.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang, M., A. Heldin, M. Palomar-Siles, S. Ohlin, V.J.N. Bykov, and K.G. Wiman. 2017. Synergistic rescue of nonsense mutant tumor suppressor p53 by combination treatment with aminoglycosides and Mdm2 inhibitors. Frontiers in Oncology 7: 323. https://doi.org/10.3389/fonc.2017.00323.

    Article  PubMed  Google Scholar 

  38. Zhang, Y., H.J. Zhang, Z.N. Zhang, S.Y. Li, W.J. Jiang, X. Li, and J.R. Lv. 2019. LncRNA MALAT1 cessation antagonizes hypoxia/reoxygenation injury in hepatocytes by inhibiting apoptosis and inflammation via the HMGB1-TLR4 axis. Molecular Immunology 112: 22–29. https://doi.org/10.1016/j.molimm.2019.04.015.

    Article  CAS  PubMed  Google Scholar 

  39. Zhao, G., X. Shen, H. Nan, L. Yan, H. Zhao, J. Yu, and Y. Lv. 2013. Remifentanil protects liver against ischemia/reperfusion injury through activation of anti-apoptotic pathways. The Journal of Surgical Research 183 (2): 827–834. https://doi.org/10.1016/j.jss.2013.02.058.

    Article  CAS  PubMed  Google Scholar 

  40. Zhao, L.Q., and Y.L. Li. 2020. Application of dexmedetomidine combined with sufentanil in colon cancer resection and its effect on immune and coagulation function of patients. Oncology Letters 20 (2): 1288–1294. https://doi.org/10.3892/ol.2020.11643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou, H., Z.H. Zhu, Y. Liu, and Y.Y. Liu. 2020. Effects of midazolam combined with sufentanil on injury and expression of HMGB1 and NF-kappa B in rats with pancreatitis. European Review for Medical and Pharmacological Sciences 24 (4): 2102–2109.

    CAS  PubMed  Google Scholar 

  42. Zuo, Y.M., X.Q. Cheng, E.W. Gu, X.Q. Liu, L. Zhang, and Y.Y. Cao. 2014. Effect of aortic root infusion of sufentanil on ischemia-reperfusion injury in patients undergoing mitral valve replacement. Journal of Cardiothoracic and Vascular Anesthesia 28 (6): 1474–1478. https://doi.org/10.1053/j.jvca.2014.04.023.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Ling Zhou and Xinlu Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Anhui Provincial Hospital, Cheeloo College of Medicine, Shangdong University, 17 Lujiang Road, Hefei, 230000, Anhui, China

    Ling Zhou, Xinlu Yang, Shuhua Shu, Sheng Wang, Fenglin Guo, Ying Yin, Weide Zhou, Han Han & Xiaoqing Chai

Authors
  1. Ling Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinlu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuhua Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fenglin Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weide Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Han Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaoqing Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ling Zhou, Xinlu Yang, Shuhua Shu, and Sheng Wang designed this study, performed experiments, and interpreted the data. Fenglin Guo, Ying Yin, and Weide Zhou collected the data, searched the literature, and wrote the manuscript. Han Han and Xiaoqing Chai revised the manuscript. All authors read and approval the final manuscript.

Corresponding author

Correspondence to Xiaoqing Chai.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval and Consent to Participate

Animal experiments were performed in accordance with a protocol approved by the Animal Experiment Ethics Committee of the Anhui Provincial Hospital (Hefei, China).

Consent for Publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, L., Yang, X., Shu, S. et al. Sufentanil Protects the Liver from Ischemia/Reperfusion-Induced Inflammation and Apoptosis by Inhibiting ATF4-Induced TP53BP2 Expression. Inflammation 44, 1160–1174 (2021). https://doi.org/10.1007/s10753-020-01410-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-020-01410-x

KEY WORDS

Search

Navigation