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Anti-inflammatory effects of insulin regular and flunixin meglumine on endotoxemia experimentally induced by Escherichia coli serotype O55:B5 in an ovine model

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Abstract

Background

Endotoxemia is a major cause of mortality in large animals and there are several therapeutic regimens for the treatment of endotoxemia. Recent studies have suggested the anti-inflammatory effects of insulin in endotoxemic human and laboratory animal models but to the best of our knowledge there is no report on the possible therapeutic effect of insulin in large animal endotoxemia.

Objective

This experiment was conducted to evaluate the anti-inflammatory effects of insulin regular compared with flunixin meglumine on the treatment of endotoxemia in sheep.

Methods

Lipopolysaccharide from Escherichia coli was administered intravenously to ewes. Anti-inflammatory effects of flunixin meglumine (at 2.2 mg/kg) and insulin regular (at 1.5 and 3 IU/kg) were evaluated by determination of serum concentrations of acute phase proteins, inflammatory cytokines and oxidative stress biomarkers.

Results

Insulin regular at 3 IU/kg controlled the acute phase response following endotoxemia induction. The anti-inflammatory potency of insulin regular at 3 IU/kg was significantly higher than at 1.5 IU/kg and of flunixin meglumine at 2.2 mg/kg (P < 0.05).

Conclusion

Insulin regular induces its anti-inflammatory effects in a dose-dependent manner. Intravenous use of insulin regular can be a potential new therapeutic regimen for endotoxemia in large animal medicine.

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References

  1. Radostits OM, Gay CC, Hinchcliff KW, Constable PD. Toxemia and endotoxemia. In: Veterinary medicine: a text book of the diseases of cattle, horses, sheep, pigs and goats. 10th ed. Amsterdam: Elsevier; 2007. p. 53–60.

  2. Moore JN, Barton MH. Treatment of endotoxemia. Vet Clin North Am Equine Pract. 2003;19:681–95.

    Article  PubMed  Google Scholar 

  3. Dandona P, Mohanty P, Chaudhuri A, Garg R, Aljada A. Insulin infusion in acute illness. J Clin Invest. 2005;115:2069–72.

    Article  PubMed  CAS  Google Scholar 

  4. Leffler M, Hrach T, Stuerzl M, Horch RE, Herndon DN, Jeschke MG. Insulin attenuates apoptosis and exerts anti-inflammatory effects in endotoxemic human macrophages. J Surg Res. 2007;143:398–406.

    Article  PubMed  CAS  Google Scholar 

  5. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–61.

    Article  PubMed  Google Scholar 

  6. Jeschke MG, Klein D, Bolder U, Einspanier R. Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology. 2004;145:4084–93.

    Article  PubMed  CAS  Google Scholar 

  7. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–77.

    Article  PubMed  CAS  Google Scholar 

  8. Iwasaki Y, Nishiyama M, Taguchi T, Asai M, Yoshida M, Kambayashi M, Terada Y, Hashimoto K. Insulin exhibits short-term anti-inflammatory but long-term proinflammatory effects in vitro. Mol Cell Endocrinol. 2009;298:25–32.

    Article  PubMed  CAS  Google Scholar 

  9. Feldman BF, Zinkl JG, Jain NC. Schalm’s Veterinary Hematology. 1st ed. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 891–896.

  10. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70:158–69.

    PubMed  CAS  Google Scholar 

  11. Eckersall PD. Recent advances and future prospects for the use of acute phase proteins as markers of disease in animals. Rev Med Vet. 2000;151:577–84.

    CAS  Google Scholar 

  12. Petersen HH, Nielsen JP, Heegaard PMH. Application of acute phase protein measurements in veterinary clinical chemistry. Vet Res. 2004;35:163–87.

    Article  PubMed  CAS  Google Scholar 

  13. Murata H, Shimada N, Yoshioka M. Current research on acute phase proteins in veterinary diagnosis: an overview. Vet J. 2004;168:28–40.

    Article  PubMed  CAS  Google Scholar 

  14. Murata H. Stress and acute phase protein response: an inconspicuous but essential linkage. Vet J. 2007;173:473–4.

    Article  PubMed  Google Scholar 

  15. Nazifi S, Khoshvaghti A, Gheisari HR. Evaluation of serum and milk amyloid A in some inflammatory diseases of cattle. Iran J Vet Res. 2008;9:222–6.

    Google Scholar 

  16. Hickey MC, Drennan M, Early B. The effect of abrupt weaning of suckler calves on the plasma concentrations of cortisol, catecholamines, leukocytes, acute-phase proteins and in vitro interferon-gamma production. J Anim Sci. 2003;81:2847–55.

    PubMed  CAS  Google Scholar 

  17. Pineiro M, Pineiro C, Carpintero R, Morales J, Campbell FM, Eckersall PD, Toussaint MJ, Lampreave F. Characterization of the pig acute phase protein response to road transport. Vet J. 2007;173:669–74.

    Article  PubMed  CAS  Google Scholar 

  18. Gruys E, Obwolo MJ, Toussaint MJM. Diagnostic significance of the major acute phase proteins in veterinary clinical chemistry: a review. Vet Bull. 1994;64:1009–18.

    Google Scholar 

  19. Skinner JG, Roberts L. Haptoglobin as an indicator of infection in sheep. Vet Rec. 1994;134:33–6.

    Article  PubMed  CAS  Google Scholar 

  20. Heinzel FP. The role of IFN-γ in the pathology of experimental endotoxemia. J Immunol. 1990;145:2920–4.

    PubMed  CAS  Google Scholar 

  21. Satomi N, Sakurai A, Haranaka K. Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: role of glucose, insulin, and macrophages. J Natl Cancer Inst. 1985;74:1255–60.

    PubMed  CAS  Google Scholar 

  22. Das UN. Is insulin an endogenous cardioprotector? Crit Care. 2002;6:389–93.

    Article  PubMed  Google Scholar 

  23. Boichot E, Sannomiya P, Escofier N, Germain N, Fortes ZB, Lagente V. Endotoxin-induced acute lung injury in rats. Role of insulin. Pulm Pharmacol Ther. 1999;12:285–90.

    Article  PubMed  CAS  Google Scholar 

  24. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-γ: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–89.

    Article  PubMed  CAS  Google Scholar 

  25. Yazar E, Er A, Uney K, Altunok V, Elmas M. Effect of flunixin meglumine on cytokine levels in experimental endotoxemia in mice. J Vet Med A Physiol Pathol Clin Med. 2007;54:352–5.

    Article  PubMed  CAS  Google Scholar 

  26. Burchett SK, Weaver WM, Westall JA, Larsen A, Kronheim S, Wilson CB. Regulation of tumor necrosis factor/cachectin and IL-1 secretion in human mononuclear phagocytes. J Immunol. 1988;140:3473–81.

    PubMed  CAS  Google Scholar 

  27. Bauer V, Bauer F. Reactive oxygen species as mediators of tissue protection and injury. Gen Physiol Biophys. 1999;18:7–14.

    PubMed  CAS  Google Scholar 

  28. Wiryana M. The role of intensive insulin therapy in increasing superoxide dismutase (SOD) and normalizing hyperglycemia in critically ill patients. Acta Med Indones. 2009;41:59–65.

    PubMed  Google Scholar 

  29. Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol. 2003;66:1499–503.

    Article  PubMed  CAS  Google Scholar 

  30. Pastore A, Piemonte F, Locatelli M, Lo Russo A, Gaeta LM, Tozzi G, Federici G. Determination of blood total, reduced, and oxidized glutathione in pediatric subjects. Clin Chem. 2003;47:1467–9.

    Google Scholar 

  31. Podil’chalk MD, Vdovychenko VI, Terlets’ka LM. Lipid peroxidation and blood serum peroxidase activity in diseases of the hepatobiliary system. Lik Sprava. 1996;1–2:110–112.

  32. Konyalıoglu S, Er A, Uney K, Elmas M, Yazar E. Effect of flunixin meglumine on the antioxidant status in endotoxemia. Acta Vet Beograd. 2007;57:241–6.

    Article  Google Scholar 

  33. Kang S, Song J, Kang H, Kim S, Lee Y, Park D. Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells. Eur J Endocrinol. 2003;148:147–55.

    Article  PubMed  CAS  Google Scholar 

  34. Mahadev KWuX, Zilbering A, Zhu L, Lawrence JTR, Goldstein BJ. Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J Biol Chem. 2001;276:48662–48669.

    Google Scholar 

  35. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increase mortality associated with growth hormone treatment in critically ill patients. N Engl J Med. 1999;341:785–92.

    Article  PubMed  CAS  Google Scholar 

  36. Frost RA, Lang CH, Gelato MC. Transient exposure of human myoblasts to tumor necrosis factor-alpha inhibits serum and insulin-like growth factor-I stimulated protein synthesis. Endocrinology. 1997;138:4153–9.

    Article  PubMed  CAS  Google Scholar 

  37. Jeschke MG, Einspanier R, Klein D, Jauch KW. Insulin attenuates the systemic inflammatory response to thermal trauma. Mol Med. 2002;8:443–50.

    PubMed  CAS  Google Scholar 

  38. Niehof M, Streetz K, Rakemann T, Bischoff SC, Manns MP, Horn F, Trautwein C. Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3. J Biol Chem. 2001;276:9016–27.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Dr. Mohamad Javad Zamiri, the head of the Teaching Barn of the Agricultural College of Shiraz University, for his kind cooperation. The authors are also grateful to Mr. Mohamad Reza Farangi for his valuable contribution to the English revision of this manuscript and Mr. Mahdi Heidari and Mrs. Marzieh Babazadeh Dezfouli for their assistance.

Conflict of interest

The authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O box: 71345, Shiraz, Iran

    Aliasghar Chalmeh, Khalil Badiei, Mehrdad Pourjafar & Saeed Nazifi

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  1. Aliasghar Chalmeh
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  2. Khalil Badiei
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  3. Mehrdad Pourjafar
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  4. Saeed Nazifi
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Correspondence to Aliasghar Chalmeh.

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Responsible Editor: Ian Ahnfelt-Rønne.

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Chalmeh, A., Badiei, K., Pourjafar, M. et al. Anti-inflammatory effects of insulin regular and flunixin meglumine on endotoxemia experimentally induced by Escherichia coli serotype O55:B5 in an ovine model. Inflamm. Res. 62, 61–67 (2013). https://doi.org/10.1007/s00011-012-0551-6

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  • DOI: https://doi.org/10.1007/s00011-012-0551-6

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