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. 1989 Mar 1;169(3):823–832. doi: 10.1084/jem.169.3.823

Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock

PMCID: PMC2189288  PMID: 2647895

Abstract

Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat- inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.

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Selected References

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  1. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Brown P. P., Coalson J. J., Elkins R. C., Hinshaw L. B., Greenfield L. J. Hemodynamic and respiratory responses of conscious swine to Escherichia coli endotoxin. Surg Forum. 1973;24:67–68. [PubMed] [Google Scholar]
  4. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cunnion R. E., Schaer G. L., Parker M. M., Natanson C., Parrillo J. E. The coronary circulation in human septic shock. Circulation. 1986 Apr;73(4):637–644. doi: 10.1161/01.cir.73.4.637. [DOI] [PubMed] [Google Scholar]
  6. Ellrodt A. G., Riedinger M. S., Kimchi A., Berman D. S., Maddahi J., Swan H. J., Murata G. H. Left ventricular performance in septic shock: reversible segmental and global abnormalities. Am Heart J. 1985 Aug;110(2):402–409. doi: 10.1016/0002-8703(85)90163-2. [DOI] [PubMed] [Google Scholar]
  7. Goodyer A. V. Left ventricular function and tissue hypoxia in irreversible hemorrhagic and endotoxin shock. Am J Physiol. 1967 Feb;212(2):444–450. doi: 10.1152/ajplegacy.1967.212.2.444. [DOI] [PubMed] [Google Scholar]
  8. Hinshaw L. B., Archer L. T., Greenfield L. J., Guenter C. A. Effects of endotoxin on myocardial hemodynamics, performance, and metabolism. Am J Physiol. 1971 Aug;221(2):504–510. doi: 10.1152/ajplegacy.1971.221.2.504. [DOI] [PubMed] [Google Scholar]
  9. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  10. MACLEAN L. D., SPINK W. W., VISSCHER M. B., WEIL M. H. Studies on the circulatory changes in the dog produced by endotoxin from gram-negative microorganisms. J Clin Invest. 1956 Nov;35(11):1191–1198. doi: 10.1172/JCI103373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Morrison D. C., Ryan J. L. Endotoxins and disease mechanisms. Annu Rev Med. 1987;38:417–432. doi: 10.1146/annurev.me.38.020187.002221. [DOI] [PubMed] [Google Scholar]
  12. Natanson C., Danner R. L., Elin R. J., Hosseini J. M., Peart K. W., Banks S. M., MacVittie T. J., Walker R. I., Parrillo J. E. Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J Clin Invest. 1989 Jan;83(1):243–251. doi: 10.1172/JCI113866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Natanson C., Danner R. L., Fink M. P., MacVittie T. J., Walker R. I., Conklin J. J., Parrillo J. E. Cardiovascular performance with E. coli challenges in a canine model of human sepsis. Am J Physiol. 1988 Mar;254(3 Pt 2):H558–H569. doi: 10.1152/ajpheart.1988.254.3.H558. [DOI] [PubMed] [Google Scholar]
  14. Natanson C., Fink M. P., Ballantyne H. K., MacVittie T. J., Conklin J. J., Parrillo J. E. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest. 1986 Jul;78(1):259–270. doi: 10.1172/JCI112559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Okusawa S., Gelfand J. A., Ikejima T., Connolly R. J., Dinarello C. A. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest. 1988 Apr;81(4):1162–1172. doi: 10.1172/JCI113431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Parker M. M., Shelhamer J. H., Bacharach S. L., Green M. V., Natanson C., Frederick T. M., Damske B. A., Parrillo J. E. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984 Apr;100(4):483–490. doi: 10.7326/0003-4819-100-4-483. [DOI] [PubMed] [Google Scholar]
  17. Parrillo J. E., Burch C., Shelhamer J. H., Parker M. M., Natanson C., Schuette W. A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest. 1985 Oct;76(4):1539–1553. doi: 10.1172/JCI112135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Solis R. T., Downing S. E. Effects of E. coli endotoxemia on ventricular performance. Am J Physiol. 1966 Aug;211(2):307–313. doi: 10.1152/ajplegacy.1966.211.2.307. [DOI] [PubMed] [Google Scholar]
  19. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  20. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  21. Tracey K. J., Lowry S. F., Fahey T. J., 3rd, Albert J. D., Fong Y., Hesse D., Beutler B., Manogue K. R., Calvano S., Wei H. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet. 1987 May;164(5):415–422. [PubMed] [Google Scholar]

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