How much Oxidative Stress Exists Without the Liver?

Abstract

Background: Oxidative stress (OS) represents an important pathogenetic factor of acute liver failure and chronic liver diseases. To elucidate whether the liver itself is a major source of OS, the present study was performed to assess OS and antioxidant status in an anhepatic porcine model.

Methods: Six pigs underwent a total hepatectomy, five pigs were sham operated. OS and antioxidant status were evaluated by measuring plasma concentrations of malondialdehyde (MDA), xanthine oxidase (XO), superoxide dismutase (SOD) and the ferric reducing ability of plasma (FRAP). They were sampled at the start of the experiment, immediately after surgery, and then at 8 and 16 hours post hepatectomy.

Results: Increased concentrations of MDA were observed in anhepatic pigs postoperatively (p < 0.02) and 8 hours after hepatectomy (p < 0.003) compared to controls. XO activity increased soon after hepatectomy (22.6 ± 5.4 mU/L versus 3.3 ± 2.1 mU/L in sham animals, p < 0.03) but returned to normal values in the further course. SOD levels did not change during the observational period in both groups. FRAP values rose significantly in the anhepatic animals compared to control (p < 0.015). A significant positive correlation was observed between MDA levels and FRAP levels (Spearman’s ρ = 0.62; p < 0.0001).

Conclusions: These findings show that hepatectomy does not completely prevent the occurrence of OS because the production and regulation of OS are also located outside the liver.

Zusammenfassung

Hintergrund: Oxidativer Stress (OS) stellt einen wichtigen pathogenetischen Faktor beim akuten Leberversagen und bei chronischen Lebererkrankungen dar. In der vorliegenden Studie wurde OS und der antioxidative Status bei einem anhepatischen Schweinemodell gemessen, um herauszufinden, ob die Leber selbst eine entscheidende Rolle bei der Entstehung von OS spielt.

Methode: 6 Schweine wurden hepatektomiert, die Kontrollgruppe bestand aus 5 Schweinen. OS und antioxidativer Status wurden bestimmt, indem die Plasmakonzentrationen von Malondialdehyd (MDA), Xanthinoxidase (XO), Superoxiddismutase (SOD) und der eisenreduzierenden antioxidativen Kapazität (FRAP) zu Beginn des Experiments, postoperativ sowie 8 und 16 Stunden nach Hepatektomie gemessen wurden.

Ergebnisse: Erhöhte MDA-Konzentrationen wurden bei den anhepatischen Tieren postoperativ (p < 0,02) und nach 8 Stunden (p < 0,003) im Vergleich zur Kontrolle beobachtet. Die XO-Aktivität nahm postoperativ zu (p < 0,03 vs. Kontrolle), kehrte jedoch im weiteren Verlauf auf Normalwerte zurück. Es fanden sich keine Veränderungen der SOD-Werte in beiden Gruppen. FRAP-Bestimmungen nahmen signifikant zu gegenüber der Kontrolle (p < 0,015). Es bestand eine positive Korrelation zwischen MDA- und FRAP-Werten (Spearman’s ρ = 0,62; p < 0,0001).

Schlussfolgerung: Diese Ergebnisse zeigen, dass das Auftreten von OS durch eine Hepatektomie nicht verhindert werden kann, da sowohl die Produktion als auch die Regulation auch außerhalb der Leber stattfinden.

Schlüsselwörter

Leber - akutes Leberversagen - Hepatektomie - oxidativer Stress

Key words

liver - acute hepatic failure - hepatectomy - oxidative stress

• References

• 1 Ringe B, Lubbe N, Kuse E et al. Total hepatectomy and liver transplantation as two-stage procedure. Ann Surg 1993; 218 (01) 3-9
• 2 Ringe B, Pichlmayr R, Lubbe N et al. Total hepatectomy as temporary approach to acute hepatic or primary graft failure. Transplant Proc 1988; 20 (01) 552-557
• 3 Arora H, Thekkekandam J, Tesche L et al. Long-term survival after 67 hours of anhepatic state due to primary liver allograft nonfunction. Liver Transpl 2010; 16 (12) 1428-1433
• 4 Bhatia V, Bhardwaj P, Elikkottil J et al. A 7-day profile of oxidative stress and antioxidant status in patients with acute liver failure. Hepatol Int 2008; 2 (04) 465-470
• 5 Bajt ML, Knight TR, Lemasters JJ et al. Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci 2004; 80 (02) 343-349
• 6 Bhardwaj P, Madan K, Thareja S et al. Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease. Hepatol Int 2008; 2 (02) 202-208
• 7 Nagasaka H, Takayanagi M, Tsukahara H. Children's toxicology from bench to bed--Liver Injury (3): Oxidative stress and anti-oxidant systems in liver of patients with Wilson disease. J Toxicol Sci 2009; 34 (Suppl. 02) SP229-SP236
• 8 Madill J, Arendt BM, Aghdassi E et al. Hepatic lipid peroxidation and antioxidant micronutrients in hepatitis virus C liver recipients with and without disease recurrence. Transplant Proc 2009; 41 (09) 3800-3805
• 9 Svegliati-Baroni G, De Minicis S, Marzioni M. Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell-to-cell interaction and transition. Liver Int 2008; 28 (08) 1052-1064
• 10 Shapiro H, Ashkenazi M, Weizman N et al. Curcumin ameliorates acute thioacetamide-induced hepatotoxicity. J Gastroenterol Hepatol 2006; 21 (02) 358-366
• 11 Ritter C, Reinke A, Andrades M et al. Protective effect of N-acetylcysteine and deferoxamine on carbon tetrachloride-induced acute hepatic failure in rats. Crit Care Med 2004; 32 (10) 2079-2083
• 12 Kusmic C, Boggi U, Bellini R et al. Oxidative stress in fulminant hepatic failure: comparison of two pig models with and without liver necrosis. Hepatogastroenterology 2001; 48 (39) 762-769
• 13 Paradis V, Kollinger M, Fabre M et al. In situ detection of lipid peroxidation by-products in chronic liver diseases. Hepatology 1997; 26 (01) 135-142
• 14 Thiel C, Thiel K, Etspueler A et al. Standardized intensive care unit management in an anhepatic pig model: new standards for analyzing liver support systems. Crit Care 2010; 14 (04) R138
• 15 Knubben K, Thiel C, Schenk M et al. A new surgical model for hepatectomy in pigs. Eur Surg Res 2008; 40 (01) 41-46
• 16 Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 1996; 239 (01) 70-76
• 17 Fabris C, Pirisi M, Panozzo MP et al. Intensity of inflammatory damage and serum lipid peroxide concentrations in liver disease. J Clin Pathol 1993; 46 (04) 364-367
• 18 Notas G, Miliaraki N, Kampa M et al. Patients with primary biliary cirrhosis have increased serum total antioxidant capacity measured with the crocin bleaching assay. World J Gastroenterol 2005; 11 (27) 4194-4198
• 19 Verlaan M, Roelofs HM, van Schaik A et al. Assessment of oxidative stress in chronic pancreatitis patients. World J Gastroenterol 2006; 12 (35) 5705-5710
• 20 Karajibani M, Hashemi M, Montazerifar F et al. The status of glutathione peroxidase, superoxide dismutase, vitamins A, C, E and malondialdehyde in patients with cardiovascular disease in Zahedan, Southeast Iran. J Nutr Sci Vitaminol (Tokyo) 2009; 55 (04) 309-316
• 21 Terkeltaub R. Learning how and when to employ uricase as bridge therapy in refractory gout. J Rheumatol 2007; 34 (10) 1955-1958
• 22 Staruchova M, Collins AR, Volkovova K et al. Occupational exposure to mineral fibres. Biomarkers of oxidative damage and antioxidant defence and associations with DNA damage and repair. Mutagenesis 2008; 23 (04) 249-260
• 23 Pacher P, Nivorozhkin A, Szabo C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58 (01) 87-114
• 24 Arsalani-Zadeh R, Ullah S, Khan S et al. Oxidative stress in laparoscopic versus open abdominal surgery: a systematic review. J Surg Res 2011; 169 (01) e59-e68
• 25 Kim K, Park EY, Lee KH et al. Differential oxidative stress response in young children and the elderly following exposure to PM(2.5). Environ Health Prev Med 2009; 14 (01) 60-66
• 26 Wang Z, Holthoff JH, Seely KA et al. Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury. Am J Pathol 2012; 180 (02) 505-516
• 27 Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000; 16 (03) 534-554
• 28 Bosoi CR, Yang X, Huynh J et al. Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 2012; 52 (07) 1228-1235
• 29 Ge M, Chi X, Zhang A et al. Intestinal NF-E2-related factor-2 expression and antioxidant activity changes in rats undergoing orthotopic liver autotransplantation. Oncol Lett 2013; 6 (05) 1307-1312
• 30 Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int 2011; 31 (10) 1432-1448
• 31 Sanyal AJ, Chalasani N, Kowdley KV et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685