The Protective Effect of Zinc Against Liver Ischaemia Reperfusion Injury in a Rat Model of Global Ischaemia

Overview

Journal J Clin Exp Hepatol

Publisher Elsevier

Specialty Gastroenterology

Date 2020 May 15

PMID 32405179

Citations 3

Authors

Ernest Cheung

Mehrdad Nikfarjam

Louise Jackett

Damien M Bolton

Joseph Ischia

Oneel Patel

Affiliations

Soon will be listed here.

Abstract

Background: Ischaemia-reperfusion injury (IRI) is a major obstacle during liver transplantation and resection surgeries for cancer, with a need for effective and safe drugs to reduce IRI. Zinc preconditioning has been shown to protect against liver IRI in a partial (70%) ischaemia model. However, its efficacy against a clinically relevant Pringle manoeuvre that results in global liver ischaemia (100%) is unknown.

Aims: The aim of this study was to test the efficacy of zinc preconditioning in a rat model of global liver ischaemia.

Methods: Rats were preconditioned via subcutaneous injection of 10 mg/kg of ZnCl, 24 h and 4 h before ischaemia. Total liver ischaemia (100%) was induced by placing a clamp across the portal triad for 30 min. Liver injury was assessed by serum alanine transaminase (ALT) and aspartate transaminase (AST) levels in blood taken before ischaemia (baseline) and at 1, 2, 4, 24, 48, 72, 96 and 120 hours after ischaemia. Animals were culled after 7 days, and the harvested livers were histologically analysed.

Results: On a two-way repeated-measures analysis of variance, there was a statistically significant (p = 0.025) difference in the mean ALT levels between saline- and ZnCl-treated groups. Specifically at 24 h after ischaemia, the ALT (341 ± 99 U/L) and AST (606 ± 78 U/L) in the zinc-treated group were significantly less than the ALT (2863 ± 828 U/L) and AST (3591 ± 948 U/L) values in the saline-treated group. Zinc significantly reduced neutrophil infiltration and necrosis compared with the saline control.

Conclusion: Zinc preconditioning reduces the overall hepatocellular damage from IRI. These results lay the foundation to assess the benefit of zinc preconditioning for clinical applications.

Citing Articles

The Roles and Pathogenesis Mechanisms of a Number of Micronutrients in the Prevention and/or Treatment of Chronic Hepatitis, COVID-19 and Type-2 Diabetes Mellitus.

Sumaily K Nutrients. 2022; 14(13).

PMID: 35807813 PMC: 9268086. DOI: 10.3390/nu14132632.

Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury.

Coni P, Pichiri G, Lachowicz J, Ravarino A, Ledda F, Fanni D Molecules. 2021; 26(21).

PMID: 34771023 PMC: 8587580. DOI: 10.3390/molecules26216614.

Randomised controlled trial for high-dose intravenous zinc as adjunctive therapy in SARS-CoV-2 (COVID-19) positive critically ill patients: trial protocol.

Perera M, El Khoury J, Chinni V, Bolton D, Qu L, Johnson P BMJ Open. 2020; 10(12):e040580.

PMID: 33268419 PMC: 7712927. DOI: 10.1136/bmjopen-2020-040580.

References

Massip-Salcedo M, Zaouali M, Padrissa-Altes S, Casillas-Ramirez A, Rodes J, Rosello-Catafau J . Activation of peroxisome proliferator-activated receptor-alpha inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia-reperfusion. Hepatology. 2007; 47(2):461-72. DOI: 10.1002/hep.21935. View

BERGMEYER H, Horder M, Rej R . International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate.... J Clin Chem Clin Biochem. 1986; 24(7):497-510. View

Wetherell D, Baldwin G, Shulkes A, Bolton D, Ischia J, Patel O . Zinc ion dyshomeostasis increases resistance of prostate cancer cells to oxidative stress via upregulation of HIF1α. Oncotarget. 2018; 9(9):8463-8477. PMC: 5823553. DOI: 10.18632/oncotarget.23893. View

Chaudry I, Clemens M, Ohkawa M, Schleck S, Baue A . Restoration of hepatocellular function and blood flow following hepatic ischemia with ATP-MgCl2. Adv Shock Res. 1982; 8:177-86. View

Olthof P, van Golen R, Meijer B, van Beek A, Bennink R, Verheij J . Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(2):375-385. DOI: 10.1016/j.bbadis.2016.10.022. View

Hasselgren P, Jennische E, Fornander J, Hellman A . No beneficial effect of ATP-MgCl2 on impaired transmembrane potential and protein synthesis in liver ischemia. Acta Chir Scand. 1982; 148(7):601-7. View

Kato L, Poggetti R, Fontes B, Massarollo P, Younes R, Heimbecker A . Evaluation of the mortality rate caused by different periods of selective portal vein occlusion in rats. Acta Cir Bras. 2007; 22(4):279-84. DOI: 10.1590/s0102-86502007000400009. View

Yamauchi H, Baca I, Mittmann U, Geisen H, Salzer M . Postischemic liver damage in rats: effect of some therapeutic interventions on survival rate. Tohoku J Exp Med. 1982; 138(1):63-70. DOI: 10.1620/tjem.138.63. View

Brennan M, Sinusas A, Horvath T, COLLINS J, Harding M . Correlation between body weight changes and postoperative pain in rats treated with meloxicam or buprenorphine. Lab Anim (NY). 2009; 38(3):87-93. PMC: 2805902. DOI: 10.1038/laban0309-87. View

10.

Yang W, Chen J, Meng Y, Chen Z, Yang J . Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver. Int J Mol Sci. 2018; 19(5). PMC: 5983804. DOI: 10.3390/ijms19051302. View

11.

Ali J, Davies S, Brais R, Randle L, Klinck J, Allison M . Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes. Liver Transpl. 2014; 21(4):487-99. DOI: 10.1002/lt.24072. View

12.

Simsek A, Yagci G, Zeybek N, Gorgulu S, Kaymakcioglu N, Kesim E . Effects of portal triad occlusion on left-sided colonic anastomosis. Int Surg. 2002; 87(1):25-30. View

13.

Pavlica S, Gaunitz F, Gebhardt R . Comparative in vitro toxicity of seven zinc-salts towards neuronal PC12 cells. Toxicol In Vitro. 2009; 23(4):653-9. DOI: 10.1016/j.tiv.2009.03.003. View

14.

Jacques F, El-Hamamsy I, Fortier A, Maltais S, Perrault L, Liberman M . Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences. Eur J Cardiothorac Surg. 2011; 41(1):193-9. PMC: 3241081. DOI: 10.1016/j.ejcts.2011.04.034. View

15.

Selzner N, Rudiger H, Graf R, Clavien P . Protective strategies against ischemic injury of the liver. Gastroenterology. 2003; 125(3):917-36. DOI: 10.1016/s0016-5085(03)01048-5. View

16.

Andreani P, Hoti E, de la Serna S, Esposti D, Sebagh M, Lemoine A . Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia-reperfusion injury and clinical relevance. HPB (Oxford). 2010; 12(7):439-46. PMC: 3030752. DOI: 10.1111/j.1477-2574.2010.00194.x. View

17.

Karagulova G, Yue Y, Moreyra A, Boutjdir M, Korichneva I . Protective role of intracellular zinc in myocardial ischemia/reperfusion is associated with preservation of protein kinase C isoforms. J Pharmacol Exp Ther. 2007; 321(2):517-25. DOI: 10.1124/jpet.107.119644. View

18.

Panteghini M . Aspartate aminotransferase isoenzymes. Clin Biochem. 1990; 23(4):311-9. DOI: 10.1016/0009-9120(90)80062-n. View

19.

Eltzschig H, Eckle T . Ischemia and reperfusion--from mechanism to translation. Nat Med. 2011; 17(11):1391-401. PMC: 3886192. DOI: 10.1038/nm.2507. View

20.

Haase H, Hebel S, Engelhardt G, Rink L . The biochemical effects of extracellular Zn(2+) and other metal ions are severely affected by their speciation in cell culture media. Metallomics. 2014; 7(1):102-11. DOI: 10.1039/c4mt00206g. View