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01.01.2015 | Original Research Paper

TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats

verfasst von: Arumugam Suyavaran, Chitteti Ramamurthy, Ramachandran Mareeswaran, Ariraman Subastri, Polaki Lokeswara Rao, Chinnasamy Thirunavukkarasu

Erschienen in: Inflammation Research | Ausgabe 1/2015

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Abstract

Background and aim

Hepatic ischemia reperfusion (I/R) stimulates Kupffer cells and initiates injury through tumor necrosis factor-α (TNF-α) upregulation. Aim of this study was to compare the variable effects of reduced glutathione (GSH) pre-treatment on I/R liver injury in young and aged rats.

Methods

Wistar male rats were sorted into young (groups I–III) and aged (groups IV–VI). All groups except sham (groups I and IV) were subjected to 90-min ischemia and 2-h reperfusion. The treatment groups received 200 mg/kg bwt (groups III and VI) of GSH, 30 min prior to I/R. Variable effects of GSH were studied by transaminase activities, thiobarbituric acid-reactive substances (TBARS), GSH level, GSH/oxidized GSH (GSSG) ratio, TNF-α level, apoptotic markers and confirmed by histopathological observations.

Results

Our findings revealed that I/R inflicted more liver damage in aged rats than young rats. The GSH treatment prior to surgery significantly lowered the serum transaminase activities, hepatic TBARS level and effectively restored the GSH/GSSG ratio in both young and aged rats more remarkably in the mitochondria. Western analysis depicted that the GSH treatment effectively suppressed TNF-α expression and apoptotic markers in both young and aged rats. These findings were further confirmed by terminal deoxynucleotide transferase dUTP nick end labeling assay and histopathological observations of liver sections of young and aged rats.

Conclusion

Restoration of GSH/GSSG ratio through GSH pre-conditioning inhibits TNF-α and apoptosis in hepatic I/R injury. Hence, GSH pre-conditioning may be utilized in both young and aged individuals during liver transplantation/surgery for better post-operative outcomes.

Carden DL, Granger DN. Pathophysiology of ischemia–reperfusion injury. J Pathol. 2000;190:255–66.PubMedCrossRef

Smyrniotis VE, Kostopanagiotou GG, Contis JC, Farantos CI, Voros DC, Kannas DC, et al. Selective hepatic vascular exclusion vs. Pringle maneuver in major liver resections: prospective study. World J Surg. 2003;27:765–9.PubMedCrossRef

Man K, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg. 1997;226:704–11.PubMedCentralPubMedCrossRef

Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion in liver transplantation. Transpl Proc. 2005;37:1653–6.CrossRef

Rymsa B, Wang JF, de Groot H. O ₂ ^.- release by activated Kupffer cells upon hypoxia–reoxygenation. Am J Physiol. 1991;261:G602–7.PubMed

Tomiyama K, Ikeda A, Ueki S, Nakao A, Stolz DB, Koike Y, et al. Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats. Hepatology. 2008;48:1608–20.PubMedCrossRef

Essani NA, McGuire GM, Manning AM, Jaeschke H, et al. Endotoxin-induced activation of the nuclear transcription factor kappa-B and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells and endothelial cells in vivo. J Immunol. 1996;156:2956–63.PubMed

Hansford RG, Hogue BA, Mildaziene V. Dependence of H₂O₂ formation by rat heart mitochondria on substrate availability and donor age. J Bioenerg Biomembr. 1997;29:89–95.PubMedCrossRef

Miquel J, Economos CA, Fleming J, Johnson JE Jr. Mitochondrial role in cell aging. Exp Gerontol. 1980;15:575–91.PubMedCrossRef

10.

Kim HG, Hong SM, Kim SJ, Paark HJ, Lee YY, Moon JS, et al. Age related changes in the activity of antioxidant and redox enzymes in rats. Mol Cells. 2003;16:278–84.PubMed

11.

Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet. 1998;34:359–73.PubMedCrossRef

12.

Strolin BM, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1:447–71.CrossRef

13.

Mallikarjuna K, Shanmugham KR, Nishanth K, Mc Wu, Hou CW, Kuo CH, et al. Alcohol-induced deterioration in primary antioxidant and glutathione family enzymes reversed by exercise training in the liver of old rats. Alcohol. 2010;44:523–9.PubMedCrossRef

14.

Castro MR, Suarez E, Kraiselburd E, Isidro A, Paz J, Ferder L, et al. Aging increases mitochondrial DNA damage and oxidative stress in liver of rhesus monkeys. Exp Gerontol. 2012;47:29–37.PubMedCentralCrossRef

15.

Sastre J, Pallardo FV, Pla R, Pellin A, Juan G, O’Connor JE, et al. Aging of the liver: age-associated mitochondrial damage in intact hepatocytes. Hepatology. 1996;24:1199–205.PubMedCrossRef

16.

Kosower NS, Kosower EM. The glutathione status of cells. Int Rev Cytol. 1978;54:109–60.PubMedCrossRef

17.

Han D, Hanawa N, Saberi B, Kaplowitz N. Mechanisms of liver injury. III. Role of glutathione redox status in liver injury. Am J Physiol Gastrointest Liver Physiol. 2006;291:G1–7.PubMedCrossRef

18.

Brass CA, Roberts TG. Hepatic free radical production after cold storage: Kupffer cell-dependent and independent mechanism in rats. Gasteroenterology. 1995;108:1167–75.CrossRef

19.

Fernandez-Checa JC, Yi JR, Ruiz CG, Ookhtens M, Kaplowitz N. Plasma membrane and mitochondrial transport of hepatic reduced glutathione. Semin Liver Dis. 1996;16:147–58.PubMedCrossRef

20.

Selzner M, Selzner N, Jochum W, Graf R, Clavien PA. Increased ischemic injury in old mouse liver: an ATP-dependent mechanism. Liv Transpl. 2007;13:382–90.CrossRef

21.

Fernandez-Checa JC, Kaplowitz N. Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol. 2005;204:263–73.PubMedCrossRef

22.

Xue F, Wang G, Pang Z, Liu C, Liang T. Protective effect of glutathione against liver warm ischemia–reperfusion injury in rats is associated with regulation of P-selectin and neutrophil infiltration. Anat Rec. 2008;291:1016–22.CrossRef

23.

Schauer RJ, Gerbes AL, Vonier D, Meissner H, Michl P, Leiderer R, et al. Glutathione protects the rat liver against reperfusion injury after prolonged warm ischemia. Ann Surg. 2004;239:220–31.PubMedCentralPubMedCrossRef

24.

Day YJ, Marshall MA, Huang L, McDuffie MJ, Okusa MD, Linden J. Protection from ischemic liver injury by activation of A–A adenosine receptors during reperfusion: inhibition of chemokine induction. Am J Physiol Gastrointest Liver Physiol. 2004;286:G285–93.PubMedCrossRef

25.

Camargo CA Jr, Madden JF, Gao W, Selvan RS, Clavien PA. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology. 1997;26:1513–20.PubMedCrossRef

26.

Ozkan E, Yardimci S, DUlundu E, et al. Protective potential of montelukast against hepatic ischemia/reperfusion injury in rats. J Surg Res. 2010;159:588–94.PubMedCrossRef

27.

Sahoo A, Chainy GB. Alterations in the activities of cerebral antioxidant enzymes of rat are related to aging. Int J Dev Neurosci. 1997;15:939–48.PubMedCrossRef

28.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.PubMedCrossRef

29.

Anaya DA, Becker NS, Abraham NS. Global graying, colorectal cancer and liver metastasis: new implications for surgical management. Crit Rev Oncol Hematol. 2011;77:100–8.PubMedCrossRef

30.

Goldberg DS, Fallon MB. Model for end-stage liver disease-based organ allocation: managing the exceptions to the rules. Clin Gastroenterol Hepatol. 2013;11:452–3.PubMedCrossRef

31.

Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation. 1992;53:957–78.PubMedCrossRef

32.

Rosser BG, Gores GJ. Liver cell necrosis: cellular mechanisms and clinical implications. Gastroenterology. 1995;108:252–75.PubMedCrossRef

33.

Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ. Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia. Free Radic Res Commun. 1991;15:277–84.PubMedCrossRef

34.

Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia–reperfusion injury in rat liver. Am J Physiol. 1991;260:G355–62.PubMed

35.

Xu SQ, Li YH, Hu SH, Chen K, Dong LY. Effect of Wy14643 on hepatic ischemia reperfusion injury in rats. World J Gastroenterol. 2008;14:6936–42.PubMedCentralPubMedCrossRef

36.

Wu C, Wang P, Rao J, Wang Z, Zhang C, Lu L, Zhang F. Triptolide alleviates hepatic ischemia/reperfusion injury by attenuating oxidative stress and inhibiting NF-κB activity in mice. J Surg Res. 2011;166:e205–13.PubMedCrossRef

37.

Lin CM, Lee JF, Chiang LL, Chen CF, Wang D, Su CL. The protective effect of curcumin on ischemia–reperfusion induced liver injury. Transplant Proc. 2012;44:974–7.PubMedCrossRef

38.

Glantzounis GK, Salacinski HJ, Yang W, Davidson BR, Seifalian AM. The contemporary role of antioxidant therapy in attenuating the ischemia–reperfusion injury: a review. Liver Transpl. 2005;11:1031–47.PubMedCrossRef

39.

Takahashi Y, Ganster RW, Gambotto A, Shao L, Kaizu T, Wu T, et al. Role of NF-kappaB on liver cold ischemia–reperfusion injury. Am J Physiol Gastrointest Liv Physiol. 2002;283:G1175–84.

40.

Crockett ET, Galligan JJ, Uhal BD, Harkema J, Roth R, Pandya K. Protection of early phase hepatic ischemia–reperfusion injury by cholinergic agonists. BMC Clin Pathol. 2006;6:3.PubMedCentralPubMedCrossRef

41.

Vardanian AJ, Busuttil RW, Kupiec-Weglinski JW. Molecular mediators of liver ischemia and reperfusion injury: a brief review. Mol Med. 2008;14:337–45.PubMedCentralPubMedCrossRef

42.

Hines IN, Harada H, Flores S, Gao B, McCord JM, Grisham MB. Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed Pharmacother. 2005;59:183–9.PubMedCrossRef

43.

Tsuchihashi S, Zhai Y, Bo Q, Busuttil RW, Kupiec Weglinski JW. Heme-oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury: inhibition of type-1 interferon signaling. Transplantation. 2007;83:1628–34.PubMedCrossRef

44.

Kaizu T, Ikeda A, Nakao A, Takahashi Y, Tsung A, Kohmoto J, et al. Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival. Hepatology. 2006;43:464–73.PubMedCrossRef

45.

Lang CA, Naryshkin S, Schneider DL, Mills BJ, Lindeman RD. Low blood glutathione in healthy aging adults. J Lab Clin Med. 1992;120:720–5.PubMed

46.

Glantzounis GK, Salacinski HJ, Yang W, Davidson BR, Seifalian AM. The contemporary role of antioxidant therapy in attenuating liver ischemia–reperfusion injury: a review. Liver Transpl. 2005;11:1031–47.PubMedCrossRef

47.

Zhang W, Wang M, Xie HY, Zhou L, Meng XQ, Shi J, et al. Role of reactive oxygen species in mediating hepatic ischemia–reperfusion injury and its therapeutic application in liver transplantation. Transplant Proc. 2007;39:1332–7.PubMedCrossRef

48.

Knight TR, Fariss MW, Farhood A, Jaeschke H. Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice. Toxicol Sci. 2003;76:229–36.PubMedCrossRef

49.

Mukhopadhyay P, Horvath B, Zsengeller Z, Batkai S, Cao Z, Kechrid M, et al. Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia–reperfusion: therapeutic potential of mitochondrially targeted antioxidants. Free Radic Biol Med. 2012;53:1123–38.PubMedCentralPubMedCrossRef

50.

Farahmand SK, Samini F, Samini M, Samarghandian S. Safarnal ameliorates antioxidant enzymes and suppresses lipid peroxidation and nitric oxide formation in aged male rat liver. Biogerontology. 2013;14:63–71.PubMedCrossRef

51.

Okajima K, Harada N, Kushimoto S, Uchiba M. Role of microthrombus formation in the development of ischemia/reperfusion-induced liver injury in rats. Thromb Haemost. 2002;88:473–80.PubMed

52.

Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24:1250–61.PubMedCentralPubMedCrossRef

53.

Mari M, Morales A, Colell A, Garcia-Ruiz C, Fernandez-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11:2685–700.PubMedCentralPubMedCrossRef

54.

Geering B, Gurzeler U, Federzoni E, Kaufmann T, Simon HU. A novel TNFR1-triggered apoptosis pathway mediated by class IA PI2Ks in neutrophils. Blood. 2011;117:5953–62.PubMedCrossRef

55.

Chaitanya GV, Alexander JS, Babu PP. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun Signal. 2010;8:31. doi:10.1186/1478-811X-8-31.PubMedCentralPubMedCrossRef

56.

Schmitt-Graff A, Kruger S, Bochard F, Gabbiani G, Denk H. Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers. Am J Pathol. 1991;138:1233–42.PubMedCentralPubMed

57.

Kim do Y, Chung SI, Ro SW, Paik YH, Lee JI, Jung MK, et al. Combined effects of an antioxidant and Caspase inhibitor on the reversal of hepatic fibrosis in rats. Apoptosis. 2013;18:1481–91.PubMedCrossRef

58.

Menger MD, Richter S, Yamauchi J. Vollmar. Role of microcirculation in hepatic ischemia/reperfusion injury. Hepato Gastroenterol. 1999;46:1452–7.

59.

Peralta C, Fernandez L, Panes J, Prats N, Sans M, Pique JM, et al. Preconditioning protects against systemic disorders associated with hepatic ischemia–reperfusion through blockade of tumor necrosis facto-induced P-selectin up-regulation in the rat. Hepatology. 2001;33:100–13.PubMedCrossRef

60.

Serbetci K, Uysal O, Erkasap N, Koken T, Baydemir C, Erkasap S. Anti-apoptotic and antioxidant effect of leptin on CCl₄ induced acute liver injury in rats. Mol Biol Rep. 2012;39:1173–80.PubMedCrossRef

Titel: TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats
verfasst von: Arumugam Suyavaran
Chitteti Ramamurthy
Ramachandran Mareeswaran
Ariraman Subastri
Polaki Lokeswara Rao
Chinnasamy Thirunavukkarasu
Publikationsdatum: 01.01.2015
Verlag: Springer Basel
Erschienen in: Inflammation Research / Ausgabe 1/2015
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-014-0785-6

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