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Melatonin protection against burn-induced liver injury. A review

  • Review Article
  • Published:
Central European Journal of Medicine

Abstract

Severe thermal injury may be complicated by dysfunction of organs distant from the original burn wound, including the liver, and represents a serious clinical problem. Although pathophysiology of burn-induced liver injury remains unclear, increasing evidence implicate activation of inflammatory response, oxidative stress, endothelial dysfunction and microcirculatory disorders as the main mechanisms of hepatic injury. Several studies suggest melatonin as a multifunctional indolamine that counteracts some of the pathophysiologic steps and displays significant beneficial effects against burn-induced cellular injury. This review summarizes the role of melatonin in restricting the burn-induced hepatic injury and focuses on its effects on oxidative stress, inflammatory response, endothelial dysfunction and microcirculatory disorders as well as on signaling pathways such as regulation of nuclear erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappaB (NF-kB). Further studies are necessary to elucidate the modulating effect of melatonin on the transcription factor responsible for the regulation of the pro-inflammatory and antioxidant genes involved in burn injuries.

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Reference

  1. Agay D., Andriollo-Sanchez M., Claeyssen R et al. Interleukin-6, TNF-alpha and interleukin-1 beta levels in blood and tissue in severely burned rats. Eur. Cytokine. Netw., 2008, 19(1), 1–7

    CAS  PubMed  Google Scholar 

  2. Jeschke M.G., Chinkes D.L., Finnerty C.C et al. Pathophysiologic response to severe burn injury. Ann. Surg., 2008, 248(3), 387–401

    PubMed Central  PubMed  Google Scholar 

  3. Yang Q., Orman M.A., Berthiaume F et al. Dynamics ofshort-term gene expression profiling in liver following thermal injury. J. Surg. Res., 2012, 176(2), 549–558

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Latha B., Babu M. The involvement of free radicals in burn injury: a review. Burns, 2001, 27, 309–317

    Article  CAS  PubMed  Google Scholar 

  5. Parihar A., Parihar M.S., Milner S., Bhat S. Oxidative stress and anti-oxidative mobilization in burn injury. Burns, 2008, 34(1), 6–17

    Article  PubMed  Google Scholar 

  6. Korkmaz A., Reiter R.J., Topal T. et al. Melatonin: an established antioxidant worthy of use in clinical trials. Mol. Med, 2009, 15(1–2), 43–50

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Rodriguez C., Mayo J.C., Sainz R.M.et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res, 2004, 36(1), 1–9

    Article  CAS  PubMed  Google Scholar 

  8. Maldonado M.D., Murillo-Cabezas F., Calvo J.R aet al. Melatonin as pharmacologic support in burn patients: a proposed solution to thermal injury-related lymphocytopenia and oxidative damage. Crit. Care Med, 2007,35, 1177–1185

    Article  CAS  PubMed  Google Scholar 

  9. Radogna F., Diederich M., Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol., 2010, 80(12), 1844–1852

    Article  CAS  PubMed  Google Scholar 

  10. Mauriz J.L., Collado P.S., Veneroso C et al. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res., 2012, May 31. doi:10.1111/j.1600-079X.2012.01014.x.

    Google Scholar 

  11. Jung K.H., Hong S.W., Zheng H.M., Lee D.H., Hong S.S. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention ofoxidative liver injury in a dimethylnitrosamine model. J Pineal Res., 2009,47(2), 173–183

    Article  CAS  PubMed  Google Scholar 

  12. El-Sokkary G.H., Abdel-Rahman G.H., Kamel E.S. Melatonin protects against lead-induced hepatic and renal toxicity in male rats. Toxicology., 2005, 213(1–2), 25–33

    Article  CAS  PubMed  Google Scholar 

  13. Chiu M.H., Su C.L., Chen C.F et al. Protective effect of melatonin on liver ischemia-reperfusion induced pulmonary microvascular injury in rats. Transplant Proc., 2012, 44(4), 962–965

    Article  CAS  PubMed  Google Scholar 

  14. Pintaudi A.M., Tesoriere L., D’Arpa N et al. Oxidative stress after moderate to extensive burning inhumans. Free Radic Res., 2000, 33(2), 139–146

    Article  CAS  PubMed  Google Scholar 

  15. Bekyarova G., Galunska B., Ivanova D., Yankova T. Effect of melatonin on burn-induced gastric mucosal injury in rats. Burns., 2009,35(6), 863–868

    Article  CAS  PubMed  Google Scholar 

  16. Sener G., Sehirli A.O., Satiroglu H et al. Melatonin improves oxidative organ damage in a rat model of thermal injury. Burns, 2002, 28, 419–425

    Article  PubMed  Google Scholar 

  17. Rawlingson A. Nitric oxide, inflammation and acute burn injury. Burns, 2003,29(7), 631–640

    Article  PubMed  Google Scholar 

  18. Bekiarova G.I., Markova M.P., Kagan V.G. [Alphatocopherol protection of erythrocytes from hemolysis induced by thermal injury]. Biull Eksp Biol Med., 1989,107(4), 413–415

    CAS  PubMed  Google Scholar 

  19. Sandre C., Agay D., Ducros V et al. Early evolution of selenium status and oxidative stress parameters in rat models of thermal injury. J Trace Elem Med Biol., 2004,17(4), 313–318

    Article  CAS  PubMed  Google Scholar 

  20. Agay D., Anderson R.A., Sandre C et al. Alterations of antioxidant trace elements (Zn, Se, Cu) and related metallo-enzymes in plasma and tissues following burn injury in rats. Burns, 2005, 31(3), 366–371

    Article  CAS  PubMed  Google Scholar 

  21. Wang B.H., Yu X.J., Wang D et al. Alterations of traceelements (Zn, Se, Cu, Fe) and related metalloenzymes in rabbit blood after severe trauma. J Trace Elem Med Biol., 2007,21(2), 102–107

    Article  CAS  PubMed  Google Scholar 

  22. Ding H.Q., Zhou B.J., Liu L., Cheng S. Oxidative stress and metallothionein expression in the liver of rats with severe thermal injury. Burns, 2002,28(3), 215–121

    Article  CAS  PubMed  Google Scholar 

  23. Pascua P., Camello-Almaraz C., Camello P.J et al. Melatonin, and to a lesser extent growth hormone, restores colonic smooth muscle physiology in old rats. J Pineal Res., 2011,51(4), 405–415

    Article  CAS  PubMed  Google Scholar 

  24. Sener G., Kabasakal L., Cetinel S et al. Leukotriene receptor blocker montelukast protects against burn-induced oxidative injury of he skin and remote organs. Burns., 2005,31(5), 587–596

    Article  PubMed  Google Scholar 

  25. Bekyarova G., Tancheva S., Hristova M. Protective effect of melatonin against oxidative hepatic injury after experimental thermal trauma, Methods Find. Exp. Clin. Pharmacol., 2009, 31, 11–14

    CAS  Google Scholar 

  26. Bekyarova G., Apostolova M., Kotzev I. Melatonin protection against burn-induced hepatic injury by down-regulation of nuclear factor kappa B activation. Int J Immunopathol Pharmacol., 2012, 25(3), 591–596

    CAS  PubMed  Google Scholar 

  27. Allegra M., Reiter R.J., Tan T.Xet al. The chemistry of melatonin’s interaction with reactive species. J Pineal Res, 2003,3, 1–10

    Article  Google Scholar 

  28. Reiter R.J., Tan D.X., Manchester L.C., Manchester W.Qi, Karbownik M., Carlo J.R., et al. Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biol Signals Recept, 2000, 9, 160–171

    Article  CAS  PubMed  Google Scholar 

  29. Antolín I., Rodríguez C., Saínz R.M et al. Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J., 1996,10(8), 882–890

    PubMed  Google Scholar 

  30. Schaffazick S.R., Pohlmann A.R., de Cordova C.A et al. Protective properties of melatonin-loaded nanoparticles against lipid peroxidation. Int J Pharm., 2005,289(1–2), 209–213

    Article  CAS  PubMed  Google Scholar 

  31. Reiter R.J., Tan D.X., Sainz R.M et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol., 2002,54(10), 1299–321

    Article  CAS  PubMed  Google Scholar 

  32. Dahiya P. Burns as a model of SIRS. Front Biosci., 2009, 14, 4962–4967

    Article  CAS  Google Scholar 

  33. Fang W.H., Yao Y.M., Shi Z.G et al. The mRNA expression patterns of tumor necrosis factor-alpha and TNFR-I in some vital organs after thermal injury. World J Gastroenterol., 2003,9(5), 1038–1044

    CAS  PubMed  Google Scholar 

  34. Sun B.W., Sun Y., Sun Z.W., Chen X. CO liberated from CORM-2 modulates the inflammatory response in the liver of thermally injured mice. World J Gastroenterol., 2008, 14(4), 547–553

    Article  CAS  PubMed  Google Scholar 

  35. Işeri S.O., Düşünceli F., Erzik C et al. Oxytocin or social housing alleviates local burn injury in rats. J Surg Res., 2010,162(1), 122–131

    Article  PubMed  Google Scholar 

  36. Horton J.W. Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. Toxicology., 2003,189(1–2), 75–88

    Article  CAS  PubMed  Google Scholar 

  37. Nishiura T., Nishimura T., deSerres S et al. Gene expression and cytokine and enzyme activation in the liver after a burn injury. J Burn Care Rehabil., 2000, 21(2), 35–141

    Article  Google Scholar 

  38. Wullaert A., van Loo G., Heyninck K et al. Hepatic tumor necrosis factor signaling and nuclear factorkappaB: effects on liver homeostasis and beyond. Endocr Rev., 2007,28(4), 365–386

    Article  CAS  PubMed  Google Scholar 

  39. Ulrich D., Noah E.M., Pallua N. [Plasma endotoxin, procalcitonin, C-reactive protein, and organ functions in patients with major burns]. Handchir Mikrochir Plast Chir., 2001, 33(4), 262–266

    Article  CAS  PubMed  Google Scholar 

  40. Haider D.G., Leuchten N., Schaller G et al. C-reactive protein is expressed and secreted by peripheral blood mononuclear cells. Clin Exp Immunol., 2006,146(3), 533–539

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Li J.Y., Yin H.Z., Gu X et al. Melatonin protects liver from intestine ischemia reperfusion injury in rats. World J Gastroenterol, 2008, 14, 7392–7396

    Article  CAS  PubMed  Google Scholar 

  42. Hu S., Yin S., Jiang X et al. Melatonin protects against alcoholic liver injury by attenuating oxidative stress, inflammatory response, and apoptosis. Eur J Pharmacol., 2009, 616(1–3), 287–92

    Article  CAS  PubMed  Google Scholar 

  43. Gravante G., Delogu D., Sconocchia G. “Systemic apoptotic response” after thermal burns. Apoptosis, 2007, 12, 259–270

    Article  CAS  PubMed  Google Scholar 

  44. Jeschke M.G., Low J.F., Spies M et al. Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. Am J Physiol Gastrointest Liver Physiol., 2001, 280(6), G1314–320

    CAS  PubMed  Google Scholar 

  45. Jaeschke H., Bajt M.L. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci., 2006, 89(1), 31–41

    Article  CAS  PubMed  Google Scholar 

  46. Muriel P. Role of free radicals in liver diseases. Hepatol Int, 2009, 3, 526–536

    Article  PubMed  Google Scholar 

  47. Acuña Castroviejo D., López L.C., Escames G et al. Melatonin mitochondria interplay in health and disease. Curr Top Med Chem., 2011,11(2), 221–240

    Article  PubMed  Google Scholar 

  48. Radogna F., Cristofanon S., Paternoster L et al. Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2. J Pineal Res., 2008,44(3), 316–325

    Article  CAS  PubMed  Google Scholar 

  49. Lucken-Ardjomande S., Martinou J.C. Regulation of Bcl-2 proteins and of the permeability of the outer mitochondrial membrane. C R Biol., 2005, 328(7), 616–631

    Article  CAS  PubMed  Google Scholar 

  50. Cristofanon S., Uguccioni F., Cerella C et al. Intracellular prooxidant activity of melatonin induces a survival pathway involving NF kappaB activation. Ann N Y Acad Sci., 2009, 1171, 472–478

    Article  CAS  PubMed  Google Scholar 

  51. Zheng H., Chen X.L., Han Z.X et al. Effect of Ligustrazine on liver injury after burn trauma. Burns, 2006,32(3), 328–334

    Article  PubMed  Google Scholar 

  52. Barnes P.J., Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med., 1997,336(15), 1066–1071

    Article  CAS  PubMed  Google Scholar 

  53. Verma S., Badiwala M.V., Weisel R.D et al. C-reactive protein activates the nuclear factorkappaB signal transduction pathway in saphenous vein endothelial cells: implications for atherosclerosis and restenosis. J Thorac Cardiovasc Surg., 2003,126(6), 1886–1891

    Article  CAS  PubMed  Google Scholar 

  54. Li J.H., Yu J.P., Yu H.G et al. Melatonin reduces inflammatory injury through inhibiting NF-kappa B activation in rats with colitis. Mediators of Inflamm, 2005, 2005(4), 185–193

    Article  Google Scholar 

  55. Sahib A.S., Al-Jawad F.H., Al-Kaisy A.A. Burns, endothelial dysfunction, and oxidative stress: the role of antioxidants. Ann Burns Fire Disasters., 2009, 22(1), 6–11

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Lum H., Roebuck K.A.: Oxidative stress and endothelial cell dysfunction. Am. J. Physiol. Cell. Physiol., 2001, 280, C719–C41

    CAS  PubMed  Google Scholar 

  57. Goligorsky M.S. Endothelial cell dysfunction: Can’t live with it, how to live without it. Am. J. Physiol. Renal. Physiol., 2005, 288, F871–880

    Article  CAS  PubMed  Google Scholar 

  58. Dhainaut J.F., Marin N., Mignon A., Vinsonneau C. Hepatic response to sepsis: Interaction between coagulation and inflammatory processes. Crit Care Med, 2001, 29(7), S2–47

    Google Scholar 

  59. Nan B., Yang H., Yan S et al. Creactive protein decreases expression of thrombomodulin and endothelial protein C receptor in human endothelial cells. Surgery, 2005, 138(2), 212–222

    Article  PubMed  Google Scholar 

  60. Bekyarova G., Tancheva S., Hristova M. The effects of melatonin on burn-induced inflammatory responses and coagulation disorders in rats. Methods Find Exp Clin Pharmacol., 2010, 32(5), 299–303

    Article  CAS  PubMed  Google Scholar 

  61. Tunali T., Sener G., Yarat A., Emekli N. Melatonin reduces oxidative damage to skin and normalizes blood coagulation in a rat model of thermal injury. Life Sci, 2005, 76(11), 1259–1265

    Article  CAS  PubMed  Google Scholar 

  62. Bekyarova G., Yankova T., Kozarev I., Yankov D. Reduced erythrocyte deformability related to activated lipid peroxidation during the early postburn period. Burns, 1996,22, 291–294

    Article  CAS  PubMed  Google Scholar 

  63. Bekyarova G. Relationship between enhanced platelet aggregation and oxidative alteration of erythrocytes in the early phase after thermal injury. Pathophysiology, 1998, 5,suppl. 1, 180–180

    Google Scholar 

  64. Levin G.Y., Egorihina M.N. The role of fibrinogen in aggregation of platelets in burn injury. Burns, 2010,36(6), 806–810

    Article  CAS  PubMed  Google Scholar 

  65. Park S.W., Choi S.M., Lee S.M. Effect of melatonin on altered expression of vasoregulatory genes during hepatic ischemia/reperfusion. Arch Pharm Res., 2007,30(12), 1619–1624

    Article  CAS  PubMed  Google Scholar 

  66. Lausevic Z., Lausevic M., Trbojevic-Stankovic J et al. Predicting multiple organ failure in patients with severe trauma. Can J Surg., 2008, 51(2), 97–102

    PubMed Central  PubMed  Google Scholar 

  67. Jeschke M.G. The hepatic response to thermal injury: is the liver important for postburn outcomes? Mol Med., 2009, 15(9–10), 337–351

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Jeschke M.G., Micak R.P., Finnerty C.C., Herndon D.N. Changes in liver function and size after a severe thermal injury. Shock, 2007, 28(2), 172–177

    Article  PubMed  Google Scholar 

  69. Ryter S.W., Otterbein L.E., Morse D., Choi A.M. Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem., 2002,234–235(1–2), 249–263

    Article  PubMed  Google Scholar 

  70. Devey L., Ferenbach D., Mohr E et al. Tissueresident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism. Mol Ther., 2009, 17, 65–72

    Article  CAS  PubMed  Google Scholar 

  71. Kamimoto M., Mizuno S., Matsumoto K., Nakamura T. Hepatocyte growth factor prevents multiple organ injuries in endotoxemic mice through a heme oxygenase-1-dependent mechanism. Biochem Biophys Res Commun; 2009, 6,380, 333–337

    Article  Google Scholar 

  72. Nakahira K., Takahashi T., Shimizu H et al. Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity. Biochem Pharmacol., 2003, 66, 1091–1105

    Article  CAS  PubMed  Google Scholar 

  73. Nakae H., Inaba H. Expression of heme oxygenase-1 in the lung and liver tissues in a rat model of burns. Burns, 2002, 28(4), 305–309

    Article  PubMed  Google Scholar 

  74. Grochot-Przeczek A., Dulak J., Jozkowicz A. Haem oxygenase-1: non-canonical roles in physiology and pathology. Clin Sci (Lond)., 201, 122(3), 93–103

  75. Piantadosi C.A, Carraway M.S, Suliman H.B. Carbon monoxide, oxidative stress, and mitochondrial permeability pore transition. Free Radic Biol Med., 2006, 15, 1332–1339

    Article  Google Scholar 

  76. Soares M.P., Seldon M.P., Gregoire I.P et al. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial activation. J Immunol., 2004, 172, 3553–3563

    CAS  PubMed  Google Scholar 

  77. Sass G., Soares M.C., Yamashita K et al. Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. Hepatology, 2003, 38, 909–918

    CAS  PubMed  Google Scholar 

  78. Otterbein L. E., Bach F. H., Alam J et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat. Med., 2000, 6, 422–428

    Article  CAS  PubMed  Google Scholar 

  79. Lee T.S., Chau L.Y. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med., 2002;8(3), 240–246

    Article  CAS  PubMed  Google Scholar 

  80. Morisaki H., Katayama T., Kotake Y et al. Carbon monoxide modulates endotoxin-induced microvascular leukocyte adhesion through platelet-dependent mechanisms. Anesthesiology, 2002, 97(3), 701–709

    Article  CAS  PubMed  Google Scholar 

  81. Durante W. Carbon monoxide and bile pigments: surprising mediators of vascular function. Vasc Med., 2002, 7(3), 195–202

    Article  PubMed  Google Scholar 

  82. Wunder C., Potter R.F. The heme oxygenase system: its role in liverinflammation. Curr Drug Targets Cardiovasc Haematol Disord., 2003, 3(3), 199–208

    Article  CAS  PubMed  Google Scholar 

  83. Searles C.D. Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression. Am J Physiol Cell Physiol., 2006,291(5), C803–816

    Article  CAS  PubMed  Google Scholar 

  84. Bach F.H. Heme oxygenase-1 as a protective gene. Wien Klin Wochenschr., 2002,114Suppl 4, 1–3

    CAS  PubMed  Google Scholar 

  85. Alam J., Cook JL. Transcriptional regulation of the heme oxygenase-1 gene via the stress response pathway. Curr Pharm Des., 2003, 9, 2499–2511

    Article  CAS  PubMed  Google Scholar 

  86. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol., 2013, 53, 401–426

    Article  CAS  PubMed  Google Scholar 

  87. Crespo I., Miguel B.S., Laliena A et al. Melatonin prevents the decreased activity of antioxidant enzymes and activates nuclear erythroid 2-related factor 2 signaling in an animal model of fulminant hepatic failure of viral origin. J Pineal Res., 2010, 49(2), 193–200

    CAS  PubMed  Google Scholar 

  88. Niture S.K., Jaiswal A.K. Nrf2-induced anti-apoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med., 2012 Dec 27. doi:pii: S0891-5849(12)01864-3

    Google Scholar 

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Authors and Affiliations

  1. Division of Pathophysiology, Medical University, Varna, Bulgaria

    Ganka Bekyarova, Minka Hristova & Krasimir Hristov

  2. Department of General and Clinical Pathology, Medical University-Varna, Varna, Bulgaria

    Maria Tzaneva

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  1. Ganka Bekyarova
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  2. Maria Tzaneva
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Correspondence to Ganka Bekyarova.

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Bekyarova, G., Tzaneva, M., Hristova, M. et al. Melatonin protection against burn-induced liver injury. A review. cent.eur.j.med 9, 148–158 (2014). https://doi.org/10.2478/s11536-013-0253-7

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  • DOI: https://doi.org/10.2478/s11536-013-0253-7

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