Oxidative Stress in Animal Models with Special Reference to Experimental Porcine Endotoxemia

  • Miklós Lipcsey
  • Mats ErikssonEmail author
  • Samar Basu
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Animal experiments offer a unique possibility to tailor study design and to standardize the experiment in a way that allows us to repeat challenges, monitoring and interventions according to scientific rationale. The animal models described in this chapter are thought to replicate human disorders where oxidative stress is a major component. These experimental settings are focused on inflammatory diseases, with particular focus on sepsis models, each animal model having its own advantages and disadvantages. Depending on the study rationale, it is possible to use specific animal models. In studies where the role of the genetic expression is thought to be evaluated, knockout mice are of utmost importance for the understanding of the synthesis of a functional gene product. When biological variables are used to determine and evaluate pathophysiological events, it is essential to know that the bioassay is applicable as well as knowledge to interpret detection limits and potential cross-reactions to other related compounds. Since inflammatory challenges differ between various types of animals, responses may not exactly reflect the reactions that occur in man. Species differences in both the innate immune systems, which offer immediate defense against infection in a nonspecific fashion, and the adaptive immune responses, which provide the vertebrate immune system with the capability to distinguish and recall identifiable pathogens are important limitations. Cascade systems and receptor expression are other examples where interpretative care must be taken. Nevertheless, animal models offer a unique ­possibility to study serious reactions and events, which are generally impossible to induce experimentally in man.


Inflammation Isoprostanes LPS Oxidative stress Prostaglandins Sepsis 


  1. 1.
    Redl H, Bahrami S, Schlag G, Traber DL. Clinical detection of LPS and animal models of endotoxemia. Immunobiology 1993;187:330–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Michie HR. The value of animal models in the development of new drugs for the treatment of the sepsis syndrome. J Antimicrob Chemother 1998;41 Suppl A:47–9.PubMedCrossRefGoogle Scholar
  3. 3.
    van Eijk LT, Pickkers P, Smits P, Bouw MP, van der Hoeven JG. Severe vagal response after endotoxin administration in humans. Intensive Care Med 2004;30:2279–81.PubMedCrossRefGoogle Scholar
  4. 4.
    Taveira da Silva AM, Kaulbach HC, Chuidian FS, Lambert DR, Suffredini AF, Danner RL. Brief report: shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. N Engl J Med 1993;328:1457–60.CrossRefGoogle Scholar
  5. 5.
    Kuriyama T, Wagner Jr WW. Collateral ventilation may protect against high-altitude pulmonary hypertension. J Appl Physiol 1981;51:1251–6.PubMedGoogle Scholar
  6. 6.
    Dodds WJ, Abelseth MK. Criteria for selecting the animal to meet the research need. Lab Anim Sci 1980;30:460–5.PubMedGoogle Scholar
  7. 7.
    Bengtsson A, Redl H, Paul E, Schlag G, Mollnes TE, Davies J. Complement and leukocyte activation in septic baboons. Circ Shock 1993;39:83–8.PubMedGoogle Scholar
  8. 8.
    Gasbarrini A, Addolorato G, Di Campli C, et al. Gender affects reperfusion injury in rat liver. Dig Dis Sci 2001;46:1305–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Xu K, Sun X, Puchowicz MA, LaManna JC. Increased sensitivity to transient global ischemia in aging rat brain. Adv Exp Med Biol 2007;599:199–206.PubMedCrossRefGoogle Scholar
  10. 10.
    Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2005;2:396–409.PubMedCrossRefGoogle Scholar
  11. 11.
    Abe S, Tanaka Y, Fujise N, et al. An antioxidative nutrient-rich enteral diet attenuates lethal activity and oxidative stress induced by lipopolysaccharide in mice. JPEN J Parenter Enteral Nutr 2007;31:181–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Russell WMS, Burch RL. The principles of humane experimental technique. London,: Methuen; 1959.Google Scholar
  13. 13.
    Basu S, Mutschler DK, Larsson AO, Kiiski R, Nordgren A, Eriksson MB. Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock. Resuscitation 2001;50:341–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Lipcsey M, Soderberg E, Basu S, et al. F2-isoprostane, inflammation, cardiac function and oxygenation in the endotoxaemic pig. Prostaglandins Leukot Essent Fatty Acids 2008;78:209–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Basu S, Eriksson M. Vitamin E in relation to lipid peroxidation in experimental septic shock. Prostaglandins Leukot Essent Fatty Acids 2000;62:195–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Arkovitz MS, Wispe JR, Garcia VF, Szabo C. Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia. J Pediatr Surg 1996;31:1009–15.PubMedCrossRefGoogle Scholar
  17. 17.
    Kristof AS, Goldberg P, Laubach V, Hussain SN. Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury. Am J Respir Crit Care Med 1998;158:1883–9.PubMedGoogle Scholar
  18. 18.
    Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–55.Google Scholar
  19. 19.
    Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 2000:13:110–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Reddy RC, Chen GH, Tateda K, et al. Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol 2001;281:L537–43.PubMedGoogle Scholar
  21. 21.
    Basu S, Eriksson M. Oxidative injury and survival during endotoxemia. FEBS Lett 1998;438:159–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Basu S, Eriksson M. Lipid peroxidation induced by an early inflammatory response in endotoxaemia. Acta Anaesthesiol Scand 2000;44:17–23.PubMedCrossRefGoogle Scholar
  23. 23.
    Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000;406:782–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson KV. Toll signaling pathways in the innate immune response. Curr Opin Immunol 2000;12:13–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Beutler B, Poltorak A. Positional cloning of Lps, and the general role of toll-like receptors in the innate immune response. Eur Cytokine Netw 2000;11:143–52.PubMedGoogle Scholar
  26. 26.
    Brightbill HD, Modlin RL. Toll-like receptors: molecular mechanisms of the mammalian immune response. Immunology 2000;101:1–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Engstrom Y. Induction and regulation of antimicrobial peptides in Drosophila. Dev Comp Immunol 1999;23:345–58.PubMedCrossRefGoogle Scholar
  28. 28.
    Imler JL, Hoffmann JA. Signaling mechanisms in the antimicrobial host defense of Drosophila. Curr Opin Microbiol 2000;3:16–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Kopp EB, Medzhitov R. The Toll-receptor family and control of innate immunity. Curr Opin Immunol 1999;11:13–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Qureshi ST, Gros P, Malo D. Host resistance to infection: genetic control of lipopolysaccharide responsiveness by TOLL-like receptor genes. Trends Genet 1999;15:291–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Wasserman SA. Toll signaling: the enigma variations. Curr Opin Genet Dev 2000;10:497–502.PubMedCrossRefGoogle Scholar
  32. 32.
    Hitchcock PJ, Leive L, Makela PH, Rietschel ET, Strittmatter W, Morrison DC. Lipopolysaccharide nomenclature--past, present, and future. J Bacteriol 1986;166:699–705.PubMedGoogle Scholar
  33. 33.
    Qureshi N, Takayama K, Kurtz R. Diphosphoryl lipid A obtained from the nontoxic lipopolysaccharide of Rhodopseudomonas sphaeroides is an endotoxin antagonist in mice. Infect Immun 1991;59:441–4.PubMedGoogle Scholar
  34. 34.
    Pridmore AC, Wyllie DH, Abdillahi F, et al. A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. J Infect Dis 2001;183:89–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Holst O, Ulmer AJ, Brade H, Flad HD, Rietschel ET. Biochemistry and cell biology of bacterial endotoxins. FEMS Immunol Med Microbiol 1996;16:83–104.PubMedCrossRefGoogle Scholar
  36. 36.
    Devoe IW, Gilchrist JE. Release of endotoxin in the form of cell wall blebs during in vitro growth of Neisseria meningitidis. J Exp Med 1973;138:1156–67.PubMedCrossRefGoogle Scholar
  37. 37.
    Hoekstra D, van der Laan JW, de Leij L, Witholt B. Release of outer membrane fragments from normally growing Escherichia coli. Biochim Biophys Acta 1976;455:889–99.PubMedCrossRefGoogle Scholar
  38. 38.
    Jorgensen JH, Smith RF. Measurement of bound and free endotoxin by the Limulus assay. Proc Soc Exp Biol Med 1974;146:1024–31.PubMedGoogle Scholar
  39. 39.
    Sjolin J, Goscinski G, Lundholm M, Bring J, Odenholt I. Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release. Clin Microbiol Inf 2000;6:74–81.CrossRefGoogle Scholar
  40. 40.
    Cooper NR, Morrison DC. Binding and activation of the first component of human complement by the lipid A region of lipopolysaccharides. J Immunol 1978;120:1862–8.PubMedGoogle Scholar
  41. 41.
    Freudenberg MA, Galanos C. Interaction of lipopolysaccharides and lipid A with complement in rats and its relation to endotoxicity. Infect Immun 1978;19:875–82.PubMedGoogle Scholar
  42. 42.
    Galanos C, Rietschel ET, Luderitz O, Westphal O. Interaction of lipopolysaccharides and lipid A with complement. Eur J Biochem 1971;19:143–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Vukajlovich SW. Antibody-independent activation of the classical pathway of human serum complement by lipid A is restricted to re-chemotype lipopolysaccharide and purified lipid A. Infect Immun 1986;53:480–5.PubMedGoogle Scholar
  44. 44.
    Haziot A, Chen S, Ferrero E, Low MG, Silber R, Goyert SM. The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J Immunol 1988;141:547–52.PubMedGoogle Scholar
  45. 45.
    Kitchens RL. Role of CD14 in cellular recognition of bacterial lipopolysaccharides. Chem Immunol 2000;74:61–82.PubMedCrossRefGoogle Scholar
  46. 46.
    Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 2000;164:5998–6004.PubMedGoogle Scholar
  47. 47.
    Muzio M, Polentarutti N, Bosisio D, Prahladan MK, Mantovani A. Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes. J Leukoc Biol 2000;67:450–6.PubMedGoogle Scholar
  48. 48.
    Zhang FX, Kirschning CJ, Mancinelli R, et al. Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 1999;274:7611–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Antal-Szalmas P, Strijp JA, Weersink AJ, Verhoef J, Van Kessel KP. Quantitation of surface CD14 on human monocytes and neutrophils. J Leukoc Biol 1997;61:721–8.PubMedGoogle Scholar
  50. 50.
    Parker SJ, Watkins PE. Experimental models of gram-negative sepsis. Br J Surg 2001;88:22–30.PubMedCrossRefGoogle Scholar
  51. 51.
    Fiorini RN, Shafizadeh SF, Polito C, et al. Anti-endotoxin monoclonal antibodies are protective against hepatic ischemia/reperfusion injury in steatotic mice. American journal of transplantation 2004;4:1567–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Giacometti A, Cirioni O, Ghiselli R, et al. Antiendotoxin activity of protegrin analog IB-367 alone or in combination with piperacillin in different animal models of septic shock. Peptides 2003;24:1747–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Goscinski G, Lipcsey M, Eriksson M, Larsson A, Tano E, Sjolin J. Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock. Crit Care 2004;8:R35–R41.PubMedCrossRefGoogle Scholar
  54. 54.
    Dyson A, Singer M. Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med 2009;37:S30–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Schrauwen E, Cox E, Houvenaghel A. Escherichia coli sepsis and endotoxemia in conscious young pigs. Vet Res Commun 1988;12:295–303.PubMedCrossRefGoogle Scholar
  56. 56.
    Crocker SH, Eddy DO, Obenauf RN, Wismar BL, Lowery BD. Bacteremia: host-specific lung clearance and pulmonary failure. J Trauma 1981;21:215–20.PubMedCrossRefGoogle Scholar
  57. 57.
    Matejovic M, Krouzecky A, Martinkova V, et al. Effects of tempol, a free radical scavenger, on long-term hyperdynamic porcine bacteremia. Crit Care Med 2005;33:1057–63.PubMedCrossRefGoogle Scholar
  58. 58.
    Saetre T, Hoiby EA, Aspelin T, Lermark G, Egeland T, Lyberg T. Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock. Crit Care Med 2000;28:2697–706.PubMedCrossRefGoogle Scholar
  59. 59.
    Hubbard WJ, Choudhry M, Schwacha MG, et al. Cecal ligation and puncture. Shock 2005;24 Suppl 1:52–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Zapelini PH, Rezin GT, Cardoso MR, et al. Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 2008;8:211–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Devrim E, Avci A, Erguder IB, Karagenc N, Kulah B, Durak I. Activities of xanthine oxidase and superoxide dismutase enzymes in rat intestinal tissues in sepsis. J Trauma 2008;64:733–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Neumann B, Zantl N, Veihelmann A, et al. Mechanisms of acute inflammatory lung injury induced by abdominal sepsis. Int Immunol 1999;11:217–27.PubMedCrossRefGoogle Scholar
  63. 63.
    Zantl N, Uebe A, Neumann B, et al. Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect Immun 1998;66:2300–9.PubMedGoogle Scholar
  64. 64.
    Rodriguez ZZ, Guanche D, Alvarez RG, Rosales FH, Alonso Y, Schulz S. Preconditioning with ozone/oxygen mixture induces reversion of some indicators of oxidative stress and ­prevents organic damage in rats with fecal peritonitis. Inflamm Res 2009.Google Scholar
  65. 65.
    Goldfarb RD, Glock D, Kumar A, et al. A porcine model of peritonitis and bacteremia ­simulates human septic shock. Shock 1996;6:442–51.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Anesthesia and Intensive CareUppsala UniversityUppsalaSweden

Personalised recommendations