Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Inflammation Research
Published in: Inflammation Research 1/2015

01-01-2015 | Original Research Paper

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

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

Published in: Inflammation Research | Issue 1/2015

Login to get access

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.
Literature
1.
Carden DL, Granger DN. Pathophysiology of ischemia–reperfusion injury. J Pathol. 2000;190:255–66.PubMedCrossRef
2.
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
3.
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
4.
Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion in liver transplantation. Transpl Proc. 2005;37:1653–6.CrossRef
5.
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
6.
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
7.
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
8.
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
9.
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.
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.
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.
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
Metadata
Title
TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats
Authors
Arumugam Suyavaran
Chitteti Ramamurthy
Ramachandran Mareeswaran
Ariraman Subastri
Polaki Lokeswara Rao
Chinnasamy Thirunavukkarasu
Publication date
01-01-2015
Publisher
Springer Basel
Published in
Inflammation Research / Issue 1/2015
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-014-0785-6

Other articles of this Issue 1/2015

Inflammation Research 1/2015 Go to the issue

Original Research Paper

Effect of retinoic acid on the function of lipopolysaccharide-stimulated bone marrow stromal cells grown on titanium surfaces

Original Research Paper

Temporal study following burn injury in young rats is associated with skeletal muscle atrophy, inflammation and altered myogenic regulatory factors

Review

Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis

Original Research Paper

Low-dose mercury heightens early innate response to coxsackievirus infection in female mice

Original Research Paper

Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo

Erratum

Erratum to: Clinical associations between IL-17 family cytokines and periodontitis and potential differential roles for IL-17A and IL-17E in periodontal immunity
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits