Effects of polymyxin B on clinical signs, serum TNF-α, haptoglobin and plasma lactate concentrations in experimental endotoxaemia in sheep

Open access


Introduction: The experiment evaluated the effects of intravenous administration of polymyxin B on experimental endotoxaemia in sheep.

Material and Methods: Twenty clinically healthy fat-tailed sheep were randomly divided into: a group treated with 6,000 U/kg of polymyxin B, a group at 12,000 U/kg, and positive and negative controls. Endotoxaemia was induced by intravenous administration of lipopolysaccharide (LPS) from E. coli serotype O55:B5 at 0.5 μg/kg. polymyxin was infused intravenously along with 2.5 L of isotonic intravenous fluids at 20 mL/kg/h. The positive control group received LPS and 2.5 L of isotonic fluids, the negatives receiving just 2.5 L of isotonic fluids. Clinical signs were evaluated before and at 1.5, 3, 4.5, 6, 24, and 48 h after LPS administration. Blood was also sampled at the denoted hours and serum haptoglobin, tumour necrosis factor-α (TNF-α), and plasma lactate concentrations were assayed.

Results: The serum concentration of TNF-α in the positive control group increased significantly up to 48 h after LPS administration. The concentration of TNF-α was significantly different from those of the polymyxin B and positive control groups from 3 to 48 h; also, the concentrations of haptoglobin at different times in the polymyxin groups were lower than those of the positive control group and were significant at hours 3 to 48 (P < 0.05). Following the LPS administration, haptoglobin and TNF-α concentrations changed without significant difference between the two polymyxin B groups.

Conclusion: Polymyxin B (6,000 U/kg) restrained blood lactate concentrations. Furthermore, it significantly improved the clinical signs in endotoxaemic animals, including rectal temperature and heart and respiratory rates. Polymyxin B may be an antiendotoxic in fat-tailed sheep.

1. Bergen P.J., Li J., Rayner C.R., Nation R.L.: Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2006, 50, 1953–1958.

2. Beutler B.: Innate immune responses to microbial poisons: discovery and function of the Toll-like receptors. Annu Rev Pharmacol Toxicol 2003, 43, 609–628.

3. Beutler B., Cerami A.: Tumor necrosis, cachexia, shock, and inflammation: a common mediator. Ann Rev Biochem 1988, 57, 505–518.

4. Cardoso L.S., Araujo M.I., Góes A.M., Pacífico L.G., Oliveira R.R., Oliveira S.C.: Polymyxin B as inhibitor of LPS contamination of Schistosoma mansoni recombinant proteins in human cytokine analysis. Microb Cell Fact 2007, 6, 1–6.

5. Chalmeh A., Badiei K., Pourjafar M., Nazifi S.: Acute phase response in experimentally Escherichia coli serotype O55: B5 induced endotoxemia and its comparative treatment with dexamethasone and flunixin meglumine in Iranian fat-tailed sheep. Vet Arh 2013, 83, 301–312.

6. Chalmeh A., Badiei K., Pourjafar M., Nazifi S.: Modulation of inflammatory responses following insulin therapy in experimentally bolus intravenous Escherichia coli lipopolysaccharide serotype O55: B5 induced endotoxemia in Iranian fat-tailed sheep. Small Rumin Res 2013, 113, 283–289.

7. Eckersall P., Bell R.: Acute phase proteins: Biomarkers of infection and inflammation in veterinary medicine. Vet J 2010, 185, 23–27.

8. Ertmer C., Kampmeier T.G., Rehberg S., Morelli A., Köhler G., Lange M., Pinto B.B., Höhn C., Hahnenkamp K., Van Aken H., Westphal M.: Effects of balanced crystalloid vs. 0.9% saline-based vs. balanced 6% tetrastarch infusion on renal function and tubular integrity in ovine endotoxemic shock. Crit Care Med 2011, 39, 783–792.

9. Gough M., Hancock R., Kelly N.M.: Antiendotoxin activity of cationic peptide antimicrobial agents. Infect Immun 1996, 64, 4922–4927.

10. Hurtado F.J., Gutierrez A.M., Silva N., Fernandez E., Khan A.E., Gutierrez G.: Role of tissue hypoxia as the mechanism of lactic acidosis during E. coli endotoxemia. J Appl Physiol 1992, 72, 1895–1901.

11. Kelley D.M.: Hypovolemic shock: an overview. Crit Care Nurs Q 2005, 28, 2–19.

12. Kruse O., Grunnet N., Barfod C.: Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med 2011, 19, 74–86.

13. Mackay R., Clark C., Logdberg L., Lake P.: Effect of a conjugate of polymyxin B-dextran 70 in horses with experimentally induced endotoxemia. Am J Vet Res 1999, 60, 68–75.

14. Morresey P.R., Mackay R.J.: Endotoxin-neutralizing activity of polymyxin B in blood after IV administration in horses. Am J Vet Res 2006, 67,642–647.

15. Murata H: Stress and acute phase protein response: an inconspicuous but essential linkage. Vet J 2007, 173, 473–474.

16. Nazifi S., Khoshvaghti A., Gheisari H.: Evaluation of serum and milk amyloid A in some inflammatory diseases of cattle. Iran J Vet Res 2008, 9, 222–226.

17. Parviainen A.K., Barton M.H., Norton N.N.: Evaluation of polymyxin B in an ex vivo model of endotoxemia in horses. Am J Vet Res 2001, 62, 72–76.

18. Pineiro M., Pineiro C., Carpintero R., Morales J., Campbell F.M., Eckersall P.D., Toussaint M.J., Lampreave F.: Characterisation of the pig acute phase protein response to road transport. Vet J 2007, 173, 669–674.

19. Pristovšek P., Kidric J.: Solution structure of polymyxins B and E and effect of binding to lipopolysaccharide: an NMR and molecular modeling study. J Med Chem 1999, 42, 4604–4613.

20. Radostists O.M., Gay C.C., Hinchcliff K.W., Constable P.D: Diseases associated with bacteria. In: Veterinary Medicine, edited by W.B. Saunders, London, 2007, pp. 1094–1123.

21. Ried C., Wahl C., Miethke T., Wellnhofer G., Landgraf C., Schneider-Mergener J., Hoess A.: High affinity endotoxin-binding and neutralizing peptides based on the crystal structure of recombinant Limulus anti-lipopolysaccharide factor. J Biol Chem 1996, 271, 28120–28127.

22. Rosenstreich D., Vogel S.: Central role of macrophages in the host response to endotoxin. Microbiology, 1980, 1980, 11–15.

23. Samimi A., Hajimohammadi A., Fazeli M., Nazifi S.: Effect of dimethyl sulfoxide on clinical signs and acute phase proteins during endotoxemia induced by Escherichia coli serotype O55:B5 in sheep. Online J Vet Res 2014, 18, 188–200.

24. Shahraki A.R., Pourjafar M., Chalmeh A., Badiei K., Heidari S., Zamiri M., Nazifi S.: Attenuating the endotoxin induced acute phase response by pentoxifylline in comparison with dexamethasone and ketoprofen in sheep. Small Rumin Res 2016, 136, 156–160.

25. Skinner J., Roberts L.: Haptoglobin as an indicator of infection in sheep. Vet Rec 1994, 134, 33–36.

26. Sterling S.A., Miller W.R., Pryor J., Puskarich M.A., Jones A.E.: The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med 2015, 43, 1907–1915.

27. Steverink P., Sturk A., Rutten V., Wagenaar-Hilbers J., Klein W., Van der Velden M., Nemeth F.: Endotoxin, interleukin-6, and tumor necrosis factor concentrations in equine acute abdominal disease: relation to clinical outcome. J Endotoxin Res 1995, 2, 289–299.

28. Sykes B., Furr M.: Equine endotoxaemia-A state-of-the-art review of therapy. Aust Vet J 2005, 83, 45–50.

29. Van Miert A.S., Van Duin C.T., Wensing T.: Effects of pentoxifylline and polymyxin B on the acute-phase-response to Escherichia coli endotoxin in dwarf goats. J Vet Pharmacol Ther 1997, 20, 61–68.

30. Vassalli P.: The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992, 10, 411–452.

31. Weiss D.J., Wardrop K.J.: Schalm's veterinary hematology, John Wiley & Sons, Philadelphia, 2011.

32. Werners A., Bull S., Fink-Gremmels J.: Endotoxaemia: a review with implications for the horse. Equine Vet J 2005, 37, 371–383.

33. Wong D.M., Sponseller B.A., Alcott C.J., Agbedanu P.N., Wang C., Hsu W.H.: Effects of intravenous administration of polymyxin B in neonatal foals with experimental endotoxemia. J Am Vet Med Assoc 2013, 243, 874–881.

34. Wynn J.L., Wong H.R.: Pathophysiology and treatment of septic shock in neonates. Clin Perinatal 2010, 37, 439–479.

35. Yamamoto H., Koizumi T., Kaneki T., Fujimoto K., Kubo K., Honda T.: Direct hemoperfusion with polymyxin B-immobilized fiber improves shock and hypoxemia during endotoxemia in anesthetized sheep. J Endotoxin Res 2002, 8, 419–426.

36. Young L., Glauser M.: Gram-negative septicemia and septic shock. WB Saunders, Philadelphia, 1991.

Journal of Veterinary Research

formerly Bulletin of the Veterinary Institute in Pulawy

Journal Information

IMPACT FACTOR J Vet Res 2017: 0.811

CiteScore 2017: 0.68

SCImago Journal Rank (SJR) 2017: 0.29
Source Normalized Impact per Paper (SNIP) 2017: 0.484


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 166 166 24
PDF Downloads 81 81 15