Research Article
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Effects of Tempol in Lipopolysaccharide-Induced Liver Injury

Year 2019, Volume: 78 Issue: 2, 147 - 155, 06.12.2019

Abstract

Objective: Sepsis leads to conditions such as inflammatory and anti-inflammatory process, circulatory abnormalities, cellular and humoral reactions. Endotoxin-induced oxidative stress causes injury in the liver. The aim of this study was to evaluate the effects of a radical scavenger Tempol in lipopolysaccharide (LPS)-induced liver injury in rats. Materials and Methods: Male Wistar rats were divided into four groups: Control, LPS (15 mg/kg), LPS + Tempol group (100 mg/kg Tempol, three hours after LPS administration) and Tempol (100 mg/kg). Blood glucose and body temperature were measured during the experiment. Superoxide dismutase (SOD), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and C-reactive protein (CRP) levels were measured in plasma or liver tissue. Furthermore, histopathological changes and myeloperoxidase-stained leukocytes infiltration were assessed in liver tissue. Results: LPS caused tissue damage and leukocytes infiltration, increased AST, ALT and CRP levels, and decreased body temperature, blood glucose and SOD levels. Tempol reduced AST and ALT levels and increased SOD levels. Tempol did not prevent tissue damage, leukocytes infiltration and increment of CRP levels. There were no changes in body temperature and blood glucose levels. Conclusion: The present study suggests that tempol may have antioxidant properties in LPS-induced liver injury. These results may contribute to a better understanding of the role of tempol and basic mechanisms of underlying oxidative stressrelated liver injury for further investigations.

Supporting Institution

This study was funded by Scientific Research Projects Coordination Unit of Istanbul University

Project Number

27021 and 33876

References

  • 1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003; 29(4): 530-8.
  • 2. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005; 365(9453): 63-78.
  • 3. Minasyan H. Sepsis and septic shock: Pathogenesis and treatment perspectives. J Crit Care 2017; 40: 229-42.
  • 4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369(9): 840-51.
  • 5. Nesseler N, Launey Y, Aninat C, Morel F, Mallédant Y, Seguin P. Clinical review: The liver in sepsis. Crit Care 2012; 16(5):235.
  • 6. Woźnica EA, Inglot M, Woźnica RK, Łysenko L. Liver dysfunction in sepsis. Adv Clin Exp Med 2018; 27(4): 547-51.
  • 7. Koch A, Horn A, Dückers H, Yagmur E, Sanson E, Bruensing J, et al. Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill non-cirrhotic patients at a medical ICU. Crit Care 2011; 15(6): 266. 8. Recknagel P, Gonnert FA, Westermann M, Lambeck S, Lupp A, Rudiger A, et al. Liver dysfunction and phosphatidylinositol-3kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. PLoS Med 2012; 9(11): e1001338. 9. Wang P, Ayala A, Ba ZF, Zhou M, Perrin MM, Chaudry IH. Tumor necrosis factor-alpha produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation. Am J Physiol1993; 265(1 Pt 1): G126-32. 10. Dhainaut JF, Marin N, Mignon A, Vinsonneau C. Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med 2001; 29(7 Suppl): 42-7. 11. Garofalo AM, Lorente-Ros M, Goncalvez G, Carriedo D, BallénBarragán A, Villar-Fernández A, et al. Histopathological changes of organ dysfunction in sepsis. Intensive Care Med Exp 2019; 7(Suppl 1):45.
  • 12. Mannaa, FA, Abdel-Wahhab, KG. Physiological potential of cytokines and liver damages. Hepatoma Res 2016; 2: 131-43.
  • 13. Szabo G, Romics L Jr, Frendl G. Liver in sepsis and systemic inflammatory response syndrome. Clin Liver Dis 2002; 6(4): 104566.
  • 14. Strnad P, Tacke F, Koch A, Trautwein C. Liver - guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol 2017; 14(1): 55-66.
  • 15. Ring A, Stremmel W. The hepatic microvascular responses to sepsis. Semin Thromb Hemost 2000; 26(5): 589-94.
  • 16. Wong CH, Jenne CN, Petri B, Chrobok NL, Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol 2013; 14(8): 785-92.
  • 17. Komine S, Akiyama K, Warabi E, Oh S, Kuga K, Ishige K, et al. Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis. Sci Rep 2017; 7(1): 11977.
  • 18. Koo DJ, Chaudry IH, Wang P. Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis. J Surg Res 1999; 83(2): 151-7.
  • 19. McCuskey RS, Nishida J, McDonnell D. Effect of immunoglobulin G on the hepatic microvascular inflammatory response during sepsis. Shock 1996; 5 (1): 28-33.
  • 20. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem 1995; 64: 97-112.
  • 21. Fridovich I. Superoxide dismutases. An adaptation to a paramagnetic gas. J Biol Chem 1989; 264(14): 7761-4.
  • 22. Samuni A, Krishna CM, Riesz P, Finkelstein E, Russo A. A novel metal-free low molecular weight superoxide dismutase mimic. J Biol Chem 1988; 263(34): 17921-4.
  • 23. Wilcox CS. Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther 2010; 126(2): 119-45.
  • 24. Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membranepermeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 1998; 32(1): 59-64.
  • 25. Pınar N, Kaplan M, Özgür T, Özcan O. Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother 2018; 102: 758-64.
  • 26. Ergin B, Bezemer R, Kandil A, Demirci-Tansel C, Ince C. TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping. J Clin Transl Res 2015; 1(2): 1-13.
  • 27. Liaw WJ, Chen TH, Lai ZZ, Chen SJ, Chen A, Tzao C, et al. Effects of a membrane-permeable radical scavenger, Tempol, on intraperitoneal sepsis-induced organ injury in rats. Shock 2005; 23(1): 88-96.
  • 28. Wang W, Zolty E, Falk S, Summer S, Zhou Z, Gengaro P, et al. Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1. Am J Physiol Renal Physiol 2008; 294(3): F571-6.
  • 29. Wang W, Jittikanont S, Falk SA, Li P, Feng L, Gengaro PE, et al. Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure. Am J Physiol Renal Physiol 2003; 284(3): F532-7.
  • 30. Zacharowski K, Olbrich A, Cuzzocrea S, Foster SJ, Thiemermann C. Membrane-permeable radical scavenger, tempol, reduces multiple organ injury in a rodent model of gram-positive shock. Crit Care Med 2000; 28(6): 1953-61.
  • 31. Leach M, Frank S, Olbrich A, Pfeilschifter J, Thiemermann C. Decline in the expression of copper/zinc superoxide dismutase in the kidney of rats with endotoxic shock: effects of the superoxide anion radical scavenger, tempol, on organ injury. Br J Pharmacol 1998; 125(4): 817-25.
  • 32. Yuksel BC, Serdar SE, Tuncel A, Uzum N, Ataoglu O, Atan A, et al. Effect of tempol, a membrane-permeable radical scavenger, on mesenteric blood flow and organ injury in a murine cecal ligation and puncture model of septic shock. Eur Surg Res 2009; 43(2): 21927.
  • 33. Demirci C, Gargili A, Kandil A, Cetinkaya H, Uyaner I, Boynuegri B, et al. Inhibition of inducible nitric oxide synthase in murine visceral larva migrans: effects on lung and liver damage. Chin J Physiol 2006; 49(6): 326-34.
  • 34. Legrand M, Almac E, Mik EG, Johannes T, Kandil A, Bezemer R, et al. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. Am J Physiol Renal Physiol 2009; 296(5): F1109-17.
  • 35. Lilley E, Armstrong R, Clark N, Gray P, Hawkins P, Mason K, et al. Refinement of animal models of sepsis and septic shock. Shock 2015; 43(4): 304-16.
  • 36. Muftuoglu MA, Aktekin A, Ozdemir NC, Saglam A. Liver injury in sepsis and abdominal compartment syndrome in rats. Surg Today 2006; 36(6): 519-24.
  • 37. Li G, Liu Y, Tzeng NS, Cui G, Block ML, Wilson B, et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol 2005; 69(2): 233-40.
  • 38. Liu X, Liu R, Dai Z, Wu H, Lin M, Tian F, et al. Effect of Shenfu injection on lipopolysaccharide (LPS)-induced septic shock in rabbits. J Ethnopharmacol 2019; 234: 36-43.
  • 39. Sha J, Zhang H, Zhao Y, Feng X, Hu X, Wang C, et al. Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor. Toxicol Appl Pharmacol 2019; 364: 144-52.
  • 40. Zhou R, Chen SH, Li G, Chen HL, Liu Y, Wu HM, et al. Ultralow doses of dextromethorphan protect mice from endotoxin-induced sepsis-like hepatotoxicity. Chem Biol Interact 2019; 303: 50-6.
  • 41. Thiemermann C, Ruetten H, Wu CC, Vane JR. The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 1995; 116(7): 2845-51.
  • 42. Mészáros K, Lang CH, Bagby GJ, Spitzer JJ. Contribution of different organs to increased glucose consumption after endotoxin administration. J Biol Chem 1987; 262(23): 10965-70.
  • 43. Engin A, Zemheri M, Bukan N, Memiş L. Effect of nitric oxide on the hypoglycaemic phase of endotoxaemia. ANZ J Surg 2006; 76(6): 512-7.
  • 44. Wallington J, Ning J, Titheradge MA. The control of hepatic glycogen metabolism in an in vitro model of sepsis. Mol Cell Biochem 2008; 308(1-2): 183-92.
  • 45. Yelich MR, Witek-Janusek L. Glucose, lactate, insulin and somatostatin responses to endotoxin in developing rats. Shock 1994; 2: 438-44.
  • 46. Anavi S, Hahn-Obercyger M, Margalit R, Madar Z, Tirosh O. A novel antihypoglycemic role of inducible nitric oxide synthase in liver inflammatory response induced by dietary cholesterol and endotoxemia. Antioxid Redox Signal 2013; 19(16): 1889-901.
  • 47. Chang CK, Gatan M, Schumer W. Efficacy of anti-tumor necrosis factor polyclonal antibody on phosphoenolpyruvate carboxykinase expression in septic and endotoxemic rats. Shock 1996; 6(1): 57-60.
  • 48. Rello J, Valenzuela-Sánchez F, Ruiz-Rodriguez M, Moyano S. Sepsis: A review of advances in management. Adv Ther 2017; 34(11): 2393-411.
Year 2019, Volume: 78 Issue: 2, 147 - 155, 06.12.2019

Abstract

Project Number

27021 and 33876

References

  • 1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003; 29(4): 530-8.
  • 2. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005; 365(9453): 63-78.
  • 3. Minasyan H. Sepsis and septic shock: Pathogenesis and treatment perspectives. J Crit Care 2017; 40: 229-42.
  • 4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369(9): 840-51.
  • 5. Nesseler N, Launey Y, Aninat C, Morel F, Mallédant Y, Seguin P. Clinical review: The liver in sepsis. Crit Care 2012; 16(5):235.
  • 6. Woźnica EA, Inglot M, Woźnica RK, Łysenko L. Liver dysfunction in sepsis. Adv Clin Exp Med 2018; 27(4): 547-51.
  • 7. Koch A, Horn A, Dückers H, Yagmur E, Sanson E, Bruensing J, et al. Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill non-cirrhotic patients at a medical ICU. Crit Care 2011; 15(6): 266. 8. Recknagel P, Gonnert FA, Westermann M, Lambeck S, Lupp A, Rudiger A, et al. Liver dysfunction and phosphatidylinositol-3kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. PLoS Med 2012; 9(11): e1001338. 9. Wang P, Ayala A, Ba ZF, Zhou M, Perrin MM, Chaudry IH. Tumor necrosis factor-alpha produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation. Am J Physiol1993; 265(1 Pt 1): G126-32. 10. Dhainaut JF, Marin N, Mignon A, Vinsonneau C. Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med 2001; 29(7 Suppl): 42-7. 11. Garofalo AM, Lorente-Ros M, Goncalvez G, Carriedo D, BallénBarragán A, Villar-Fernández A, et al. Histopathological changes of organ dysfunction in sepsis. Intensive Care Med Exp 2019; 7(Suppl 1):45.
  • 12. Mannaa, FA, Abdel-Wahhab, KG. Physiological potential of cytokines and liver damages. Hepatoma Res 2016; 2: 131-43.
  • 13. Szabo G, Romics L Jr, Frendl G. Liver in sepsis and systemic inflammatory response syndrome. Clin Liver Dis 2002; 6(4): 104566.
  • 14. Strnad P, Tacke F, Koch A, Trautwein C. Liver - guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol 2017; 14(1): 55-66.
  • 15. Ring A, Stremmel W. The hepatic microvascular responses to sepsis. Semin Thromb Hemost 2000; 26(5): 589-94.
  • 16. Wong CH, Jenne CN, Petri B, Chrobok NL, Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol 2013; 14(8): 785-92.
  • 17. Komine S, Akiyama K, Warabi E, Oh S, Kuga K, Ishige K, et al. Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis. Sci Rep 2017; 7(1): 11977.
  • 18. Koo DJ, Chaudry IH, Wang P. Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis. J Surg Res 1999; 83(2): 151-7.
  • 19. McCuskey RS, Nishida J, McDonnell D. Effect of immunoglobulin G on the hepatic microvascular inflammatory response during sepsis. Shock 1996; 5 (1): 28-33.
  • 20. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem 1995; 64: 97-112.
  • 21. Fridovich I. Superoxide dismutases. An adaptation to a paramagnetic gas. J Biol Chem 1989; 264(14): 7761-4.
  • 22. Samuni A, Krishna CM, Riesz P, Finkelstein E, Russo A. A novel metal-free low molecular weight superoxide dismutase mimic. J Biol Chem 1988; 263(34): 17921-4.
  • 23. Wilcox CS. Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther 2010; 126(2): 119-45.
  • 24. Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membranepermeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 1998; 32(1): 59-64.
  • 25. Pınar N, Kaplan M, Özgür T, Özcan O. Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother 2018; 102: 758-64.
  • 26. Ergin B, Bezemer R, Kandil A, Demirci-Tansel C, Ince C. TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping. J Clin Transl Res 2015; 1(2): 1-13.
  • 27. Liaw WJ, Chen TH, Lai ZZ, Chen SJ, Chen A, Tzao C, et al. Effects of a membrane-permeable radical scavenger, Tempol, on intraperitoneal sepsis-induced organ injury in rats. Shock 2005; 23(1): 88-96.
  • 28. Wang W, Zolty E, Falk S, Summer S, Zhou Z, Gengaro P, et al. Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1. Am J Physiol Renal Physiol 2008; 294(3): F571-6.
  • 29. Wang W, Jittikanont S, Falk SA, Li P, Feng L, Gengaro PE, et al. Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure. Am J Physiol Renal Physiol 2003; 284(3): F532-7.
  • 30. Zacharowski K, Olbrich A, Cuzzocrea S, Foster SJ, Thiemermann C. Membrane-permeable radical scavenger, tempol, reduces multiple organ injury in a rodent model of gram-positive shock. Crit Care Med 2000; 28(6): 1953-61.
  • 31. Leach M, Frank S, Olbrich A, Pfeilschifter J, Thiemermann C. Decline in the expression of copper/zinc superoxide dismutase in the kidney of rats with endotoxic shock: effects of the superoxide anion radical scavenger, tempol, on organ injury. Br J Pharmacol 1998; 125(4): 817-25.
  • 32. Yuksel BC, Serdar SE, Tuncel A, Uzum N, Ataoglu O, Atan A, et al. Effect of tempol, a membrane-permeable radical scavenger, on mesenteric blood flow and organ injury in a murine cecal ligation and puncture model of septic shock. Eur Surg Res 2009; 43(2): 21927.
  • 33. Demirci C, Gargili A, Kandil A, Cetinkaya H, Uyaner I, Boynuegri B, et al. Inhibition of inducible nitric oxide synthase in murine visceral larva migrans: effects on lung and liver damage. Chin J Physiol 2006; 49(6): 326-34.
  • 34. Legrand M, Almac E, Mik EG, Johannes T, Kandil A, Bezemer R, et al. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. Am J Physiol Renal Physiol 2009; 296(5): F1109-17.
  • 35. Lilley E, Armstrong R, Clark N, Gray P, Hawkins P, Mason K, et al. Refinement of animal models of sepsis and septic shock. Shock 2015; 43(4): 304-16.
  • 36. Muftuoglu MA, Aktekin A, Ozdemir NC, Saglam A. Liver injury in sepsis and abdominal compartment syndrome in rats. Surg Today 2006; 36(6): 519-24.
  • 37. Li G, Liu Y, Tzeng NS, Cui G, Block ML, Wilson B, et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol 2005; 69(2): 233-40.
  • 38. Liu X, Liu R, Dai Z, Wu H, Lin M, Tian F, et al. Effect of Shenfu injection on lipopolysaccharide (LPS)-induced septic shock in rabbits. J Ethnopharmacol 2019; 234: 36-43.
  • 39. Sha J, Zhang H, Zhao Y, Feng X, Hu X, Wang C, et al. Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor. Toxicol Appl Pharmacol 2019; 364: 144-52.
  • 40. Zhou R, Chen SH, Li G, Chen HL, Liu Y, Wu HM, et al. Ultralow doses of dextromethorphan protect mice from endotoxin-induced sepsis-like hepatotoxicity. Chem Biol Interact 2019; 303: 50-6.
  • 41. Thiemermann C, Ruetten H, Wu CC, Vane JR. The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 1995; 116(7): 2845-51.
  • 42. Mészáros K, Lang CH, Bagby GJ, Spitzer JJ. Contribution of different organs to increased glucose consumption after endotoxin administration. J Biol Chem 1987; 262(23): 10965-70.
  • 43. Engin A, Zemheri M, Bukan N, Memiş L. Effect of nitric oxide on the hypoglycaemic phase of endotoxaemia. ANZ J Surg 2006; 76(6): 512-7.
  • 44. Wallington J, Ning J, Titheradge MA. The control of hepatic glycogen metabolism in an in vitro model of sepsis. Mol Cell Biochem 2008; 308(1-2): 183-92.
  • 45. Yelich MR, Witek-Janusek L. Glucose, lactate, insulin and somatostatin responses to endotoxin in developing rats. Shock 1994; 2: 438-44.
  • 46. Anavi S, Hahn-Obercyger M, Margalit R, Madar Z, Tirosh O. A novel antihypoglycemic role of inducible nitric oxide synthase in liver inflammatory response induced by dietary cholesterol and endotoxemia. Antioxid Redox Signal 2013; 19(16): 1889-901.
  • 47. Chang CK, Gatan M, Schumer W. Efficacy of anti-tumor necrosis factor polyclonal antibody on phosphoenolpyruvate carboxykinase expression in septic and endotoxemic rats. Shock 1996; 6(1): 57-60.
  • 48. Rello J, Valenzuela-Sánchez F, Ruiz-Rodriguez M, Moyano S. Sepsis: A review of advances in management. Adv Ther 2017; 34(11): 2393-411.
There are 44 citations in total.

Details

Primary Language English
Journal Section Research Articles
Authors

Perihan Sinem Serin This is me 0000-0001-6404-5687

Aslı Kandil 0000-0001-8408-2610

Huri Bulut This is me 0000-0003-2706-9625

Tugba Kaskavalci This is me

Erman Caner Bulut This is me

Cihan Demirci-tansel This is me

Project Number 27021 and 33876
Publication Date December 6, 2019
Submission Date September 20, 2019
Published in Issue Year 2019 Volume: 78 Issue: 2

Cite

AMA Serin PS, Kandil A, Bulut H, Kaskavalci T, Bulut EC, Demirci-tansel C. Effects of Tempol in Lipopolysaccharide-Induced Liver Injury. Eur J Biol. December 2019;78(2):147-155.