Reconciling Clinical Criteria and the Use of Genetically Engineered Animals in Sepsis Research

  • G. Albuszies
  • C. Ince
  • P. Radermacher
Conference paper


A powerful method for identifying the in vivo molecular mechanisms that underlie pathophysiologic conditions seen in sepsis and septic shock is the utilization of genetically engineered mice in a clinically relevant experimental setting. Various aspects of preclinical study design, including the type of model, have to be considered carefully according to current understandings of the cause and course of clinical sepsis. The implementation of recommended therapeutic strategies in experimental sepsis is crucial to obtain meaningful data and, therefore, achieve a proper level of relevance. Ongoing and rapid progress in the development of microsurgical techniques and methods of measurements applicable in such a small-sized species facilitate the acquisition and evaluation of objective criteria and physiological parameters, respectively. The transformation of a typical clinical setting in intensive care units (ICUs), including mechanical ventilation and invasive monitoring of organ function into experiments on mice, may become routine maneuvers.


Septic Shock Acute Lung Injury Cecal Ligation Septic Mouse Polymicrobial Sepsis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Bahar MA, Kilani RT, Ghahary A (2000) The spectrum of pathogenic bacteria in positive blood cultures. Microbios 103: 107–117PubMedGoogle Scholar
  2. 2.
    Opal SM, Cohen J (1999) Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med 27: 1608–1616PubMedCrossRefGoogle Scholar
  3. 3.
    Cross AS, Opal SM, Sadoff JC, Gemski P (1993) Choice of bacteria in animal models of sepsis. Infect Immun 61: 2741–2747PubMedGoogle Scholar
  4. 4.
    Redl H, Bahrami S, Schlag G, Traber DL (1993) Clinical detection of LPS and animal models of endotoxemia. Immunobiology 187: 330–345PubMedCrossRefGoogle Scholar
  5. 5.
    Remick DG, Newcomb DE, Bolgos GL, Call DR (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13: 110–116PubMedCrossRefGoogle Scholar
  6. 6.
    Evans GF, Snyder YM, Butler LD, Zuckerman SH (1989) Differential expression of interleukin-1 and tumor necrosis factor in murine septic shock models. Circ Shock 29: 279–290PubMedGoogle Scholar
  7. 7.
    Remick D, Manohar P, Bolgos G, Rodriguez J, Moldawer L, Wollenberg G (1995) Blockade of tumor necrosis factor reduces lipopolysaccharide lethality, but not the lethality of cecal ligation and puncture. Shock 4: 89–95PubMedCrossRefGoogle Scholar
  8. 8.
    Abraham E, Anzueto A, Gutierrez G, et al (1998) Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351: 929–933Google Scholar
  9. 9.
    Bone RC, Fisher C Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1987) A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317: 653–658PubMedCrossRefGoogle Scholar
  10. 10.
    Freise H, Bruckner UB, Spiegel HU (2001) Animal models of sepsis. J Invest Surg 14: 195212Google Scholar
  11. 11.
    Wichterman KA, Baue AE, Chaudry IH (1980) Sepsis and septic shock–a review of laboratory models and a proposal. J Surg Res 29: 189–201PubMedCrossRefGoogle Scholar
  12. 12.
    Baker CC, Chaudry IH, Gaines HO, Baue AE (1983) Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. Surgery 94: 331–335PubMedGoogle Scholar
  13. 13.
    Ebong S, Call D, Nemzek J, Bolgos G, Newcomb D, Remick D (1999) Immunopathologic alterations in murine models of sepsis of increasing severity. Infect Immun 67: 6603–6610PubMedGoogle Scholar
  14. 14.
    Lush CW, Cepinskas G, Sibbald W], Kvietys PR (2001) Endothelial E- and P-selectin expression in iNOS-deficient mice exposed to polymicrobial sepsis. Am J Physiol 280: G291 - G297Google Scholar
  15. 15.
    Walley KR, Lukacs NW, Standiford TJ, Strieter RM, Kunkel SL (1996) Balance of inflammatory cytokines related to severity and mortality of murine sepsis. Infect Immun 64: 47334738Google Scholar
  16. 16.
    Hollenberg SM, Dumasius A, Easington C, Colilla SA, Neumann A, Parrillo JE (2001) Characterization of a hyperdynamic murine model of resuscitated sepsis using echocardiography. Am J Respir Crit Care Med 164: 891–895PubMedCrossRefGoogle Scholar
  17. 17.
    Godshall CJ, Scott MJ, Peyton JC, Gardner SA, Cheadle WG (2002) Genetic background determines susceptibility during murine septic peritonitis. J Surg Res 102: 45–49PubMedCrossRefGoogle Scholar
  18. 18.
    Stewart D, Fulton WB, Wilson C, et al (2002) Genetic contribution to the septic response in a mouse model. Shock 18: 342–347PubMedCrossRefGoogle Scholar
  19. 19.
    Diodato MD, Knoferl MW, Schwacha MG, Bland KI, Chaudry IH (2001) Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. Cytokine 14: 162–169PubMedCrossRefGoogle Scholar
  20. 20.
    Hyde SR, Stith RD, McCallum RE (1990) Mortality and bacteriology of sepsis following ce-cal ligation and puncture in aged mice. Infect Immun 58: 619–624PubMedGoogle Scholar
  21. 21.
    Jimenez MF, Marshall JC (2001) Source control in the management of sepsis. Intensive Care Med 27 (suppl 1): S49 - S62PubMedCrossRefGoogle Scholar
  22. 22.
    Bochud PY, Glauser MP, Calandra T (2001) Antibiotics in sepsis. Intensive Care Med 27 (suppl 1): S33 - S48PubMedCrossRefGoogle Scholar
  23. 23.
    Newcomb D, Bolgos G, Green L, Remick DG (1998) Antibiotic treatment influences outcome in murine sepsis: mediators of increased morbidity. Shock 10: 110–117PubMedCrossRefGoogle Scholar
  24. 24.
    Vincent JL (2001) Hemodynamic support in septic shock. Intensive Care Med 27 (suppl 1): S80 - S92PubMedCrossRefGoogle Scholar
  25. 25.
    Yang S, Chung CS, Ayala A, Chaudry IH, Wang P (2002) Differential alterations in cardiovascular responses during the progression of polymicrobial sepsis in the mouse. Shock 17: 55–60PubMedCrossRefGoogle Scholar
  26. 26.
    Zuurbier CJ, Emons VM, Ince C (2002) Hemodynamics of anesthetized ventilated mouse models: aspects of anesthetics, fluid support, and strain. Am J Physiol 282: H2099 - H2105Google Scholar
  27. 27.
    Hoit BD (2001) New approaches to phenotypic analysis in adult mice. J Mol. Cell Cardiol 33: 27–35PubMedCrossRefGoogle Scholar
  28. 28.
    Wilson MA, Chou MC, Spain DA, et al (1996) Fluid resuscitation attenuates early cytokine mRNA expression after peritonitis. J Trauma 41: 622–627PubMedCrossRefGoogle Scholar
  29. 29.
    Razavi HM, Werhun R, Scott JA, et al (2002) Effects of inhaled nitric oxide in a mouse model of sepsis-induced acute lung injury. Crit Care Med 30: 868–873PubMedCrossRefGoogle Scholar
  30. 30.
    Tsujimoto H, Ono S, Mochizuki H, et al (2002) Role of macrophage inflammatory protein 2 in acute lung injury in murine peritonitis. J Surg Res 103: 61–67PubMedCrossRefGoogle Scholar
  31. 31.
    Hastings RH, Summers-Torres D (1999) Direct laryngoscopy in mice. Contemp Top Lab Anim Sci 38: 33–35PubMedGoogle Scholar
  32. 32.
    Schwarte LA, Zuurbier CJ, Ince C (2000) Mechanical ventilation of mice. Basic Res Cardiol 95: 510–520PubMedCrossRefGoogle Scholar
  33. 33.
    Tankersley CG, Fitzgerald RS, Kleeberger SR (1994) Differential control of ventilation among inbred strains of mice. Am J Physiol 267: R1371 - R1377PubMedGoogle Scholar
  34. 34.
    Martin GS, Bernard GR (2001) Airway and lung in sepsis. Intensive Care Med 27 (suppl 1): S63 - S79PubMedCrossRefGoogle Scholar
  35. 35.
    Arras M, Autenried P, Rettich A, Spaeni D, Rulicke T (2001) Optimization of intraperitoneal injection anesthesia in mice: drugs, dosages, adverse effects, and anesthesia depth. Comp Med 51: 443–456PubMedGoogle Scholar
  36. 36.
    Imai T, Takahashi K, Masuo F, Goto F (1998) Anaesthesia affects outcome of sepsis in mice. Can J Anaesth 45: 360–366PubMedCrossRefGoogle Scholar
  37. 37.
    Gades NM, Danneman PJ, Wixson SK, Tolley EA (2000) The magnitude and duration of the analgesic effect of morphine, butorphanol, and buprenorphine in rats and mice. Con-temp Top Lab Anim Sci 39: 8–13Google Scholar
  38. 38.
    Kluger MJ, Kozak W, Leon LR, Conn CA (1998) The use of knockout mice to understand the role of cytokines in fever. Clin Exp Pharmacol Physiol 25: 141–144PubMedCrossRefGoogle Scholar
  39. 39.
    Silva AT, Bayston KF, Cohen J (1990) Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative shock. J Infect Dis 162: 421–427PubMedCrossRefGoogle Scholar
  40. 40.
    Noble WC (1965) The production of subcutaneous staphylococcal skin lesions in mice. Br J Exp Pathol 46: 254–262PubMedGoogle Scholar
  41. 41.
    McConville JH, Snyder MJ, Calia FM, Hornick RB (1981) Model of intraabdominal abscess in mice. Infect Immun 31: 507–509PubMedGoogle Scholar
  42. 42.
    Strand TA, Briles DE, Gjessing HK, Maage A, Bhan MK, Sommerfelt H (2001) Pneumococcal pulmonary infection, septicaemia and survival in young zinc-depleted mice. Br J Nutr 86: 301–306PubMedCrossRefGoogle Scholar
  43. 43.
    Kim MK, Zhou W, Tessier PR, et al (2002) Bactericidal effect and pharmacodynamics of cethromycin (ABT-773) in a murine pneumococcal pneumonia model. Antimicrob Agents Chemother 46: 3185–3192PubMedCrossRefGoogle Scholar
  44. 44.
    Wang E, Ouellet N, Simard M, et al (2001) Pulmonary and systemic host response to Streptococcus pneumoniae and Klebsiella pneumoniae bacteremia in normal and immunosuppressed mice. Infect Immun 69: 5294–5304PubMedCrossRefGoogle Scholar
  45. 45.
    Weicker S, Karachi TA, Scott JA, McCormack DG, Mehta S (2001) Noninvasive measurement of exhaled nitric oxide in a spontaneously breathing mouse. Am J Respir Grit Care Med 163: 1113–1116CrossRefGoogle Scholar
  46. 46.
    Ishihara K, Oyaizu S, Mizunoya W, Fukuchi Y, Yasumoto K, Fushiki T (2002) Use of 13C-labeled glucose for measuring exogenous glucose oxidation in mice. Biosci Biotechnol Biochem 66: 426–429PubMedCrossRefGoogle Scholar
  47. 47.
    Nemoto S, Vallejo JG, Knuefermann P, et al (2002) Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart. Am J Physiol 282: H2316 - H2323Google Scholar
  48. 48.
    Kragh M, Quistorff B, Horsman MR, Kristjansen PE (2002) Acute effects of vascular modifying agents in solid tumors assessed by noninvasive laser Doppler flowmetry and near infrared spectroscopy. Neoplasia 4: 263–267PubMedCrossRefGoogle Scholar
  49. 49.
    Biberthaler P, Langer S, Luchting B, Khandoga A, Messmer K (2001) In vivo assessment of colon microcirculation: comparison of the new OPS imaging technique with intravital microscopy. Eur J Med Res 6: 525–534PubMedGoogle Scholar
  50. 50.
    Hallemeesch MM, Soeters PB, Deutz NE (2002) Renal arginine and protein synthesis are increased during early endotoxemia in mice. Am J Physiol 282: F316 - F323Google Scholar
  51. 51.
    Baykal A, Kavuklu B, Iskit AB, Guc MO, Hascelik G, Sayek I (2000) Experimental study of the effect of nitric oxide inhibition on mesenteric blood flow and interleukin-10 levels with a lipopolysaccharide challenge. World J Surg 24: 1116–1120PubMedCrossRefGoogle Scholar
  52. 1.
    Bahar MA, Kilani RT, Ghahary A (2000) The spectrum of pathogenic bacteria in positive blood cultures. Microbios 103: 107–117PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • G. Albuszies
  • C. Ince
  • P. Radermacher

There are no affiliations available

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