Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 1;98(1):192–198. doi: 10.1172/JCI118766

Efficacy of treatment with the iron (III) complex of diethylenetriamine pentaacetic acid in mice and primates inoculated with live lethal dose 100 Escherichia coli.

L Molina 1, S Studenberg 1, G Wolberg 1, W Kazmierski 1, J Wilson 1, A Tadepalli 1, A C Chang 1, S Kosanke 1, L Hinshaw 1
PMCID: PMC507416  PMID: 8690793

Abstract

The iron (III) complex of diethylenetriamine pentaacetic acid (DTPA iron [III]) protected mice and baboons from the lethal effects of an infusion with live LD100 Escherichia coli. In mice, optimal results were obtained when DTPA iron (III) was administered two or more hours after infection. Prevention of death occurred in spite of the fact that the adverse effects of TNF-alpha were well underway in the mouse model. The half-life of DTPA iron (III) was 51 +/- 9 min in normal baboons; primary clearance was consistent with glomerular filtration. In septic baboons, survival was observed after administration of two doses of DTPA iron (III) at 2.125 mg/kg, the first one given before, or as late as 2 h after, severe hypotension. Administration of DTPA iron (III) did not alter mean systemic arterial pressure, but did protect baboons in the presence of high levels of TNF-alpha and free radical overproduction. Furthermore, exaggerated production of nitric oxide was attenuated. The mechanism of protection with DTPA iron (III) is not obvious. Because of its ability to interact in vitro with free radicals, its poor cell permeability, and its short half-life, we postulate that DTPA iron (III) and/or its reduced form may have protected the mice and baboons by sequestration and subsequent elimination of free radicals (including nitric oxide) from their systems.

Full Text

The Full Text of this article is available as a PDF (179.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bellomo R. The cytokine network in the critically ill. Anaesth Intensive Care. 1992 Aug;20(3):288–302. doi: 10.1177/0310057X9202000303. [DOI] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  3. Billiau A., Vandekerckhove F. Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock. Eur J Clin Invest. 1991 Dec;21(6):559–573. doi: 10.1111/j.1365-2362.1991.tb01410.x. [DOI] [PubMed] [Google Scholar]
  4. Bone R. C., Fisher C. J., Jr, Clemmer T. P., Slotman G. J., Metz C. A., Balk R. A. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987 Sep 10;317(11):653–658. doi: 10.1056/NEJM198709103171101. [DOI] [PubMed] [Google Scholar]
  5. Brackett D. J., Lai E. K., Lerner M. R., Wilson M. F., McCay P. B. Spin trapping of free radicals produced in vivo in heart and liver during endotoxemia. Free Radic Res Commun. 1989;7(3-6):315–324. doi: 10.3109/10715768909087957. [DOI] [PubMed] [Google Scholar]
  6. Broner C. W., Shenep J. L., Stidham G. L., Stokes D. C., Hildner W. K. Effect of scavengers of oxygen-derived free radicals on mortality in endotoxin-challenged mice. Crit Care Med. 1988 Sep;16(9):848–851. doi: 10.1097/00003246-198809000-00006. [DOI] [PubMed] [Google Scholar]
  7. Calver A., Collier J., Vallance P. Nitric oxide and cardiovascular control. Exp Physiol. 1993 May;78(3):303–326. doi: 10.1113/expphysiol.1993.sp003687. [DOI] [PubMed] [Google Scholar]
  8. Chamulitrat W., Jordan S. J., Mason R. P., Litton A. L., Wilson J. G., Wood E. R., Wolberg G., Molina y Vedia L. Targets of nitric oxide in a mouse model of liver inflammation by Corynebacterium parvum. Arch Biochem Biophys. 1995 Jan 10;316(1):30–37. doi: 10.1006/abbi.1995.1006. [DOI] [PubMed] [Google Scholar]
  9. Crawley F. E., Haines J. W. The dosimetry of carbon-14 labelled compounds: the metabolism of diethylenetriamine pentaacetic acid (DTPA) in the rat. Int J Nucl Med Biol. 1979;6(1):9–15. doi: 10.1016/0047-0740(79)90061-5. [DOI] [PubMed] [Google Scholar]
  10. Demling R. H., Lalonde C., Jin L. J., Ryan P., Fox R. Endotoxemia causes increased lung tissue lipid peroxidation in unanesthetized sheep. J Appl Physiol (1985) 1986 Jun;60(6):2094–2100. doi: 10.1152/jappl.1986.60.6.2094. [DOI] [PubMed] [Google Scholar]
  11. Dinarello C. A., Thompson R. C. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today. 1991 Nov;12(11):404–410. doi: 10.1016/0167-5699(91)90142-G. [DOI] [PubMed] [Google Scholar]
  12. Doebber T. W., Wu M. S., Robbins J. C., Choy B. M., Chang M. N., Shen T. Y. Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem Biophys Res Commun. 1985 Mar 29;127(3):799–808. doi: 10.1016/s0006-291x(85)80014-0. [DOI] [PubMed] [Google Scholar]
  13. Gavellas G., Disbrow M. R., Hwang K. H., Hinkle D. K., Bourgoignie J. J. Glomerular filtration rate and blood pressure monitoring in awake baboons. Lab Anim Sci. 1987 Oct;37(5):657–662. [PubMed] [Google Scholar]
  14. Gryglewski R. J., Botting R. M., Vane J. R. Mediators produced by the endothelial cell. Hypertension. 1988 Dec;12(6):530–548. doi: 10.1161/01.hyp.12.6.530. [DOI] [PubMed] [Google Scholar]
  15. Harbrecht B. G., Billiar T. R., Stadler J., Demetris A. J., Ochoa J., Curran R. D., Simmons R. L. Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol. 1992 Oct;52(4):390–394. doi: 10.1002/jlb.52.4.390. [DOI] [PubMed] [Google Scholar]
  16. Hinshaw L. B. Application of animal shock models to the human. Circ Shock. 1985;17(3):205–212. [PubMed] [Google Scholar]
  17. Hinshaw L. B., Archer L. T., Beller-Todd B. K., Coalson J. J., Flournoy D. J., Passey R., Benjamin B., White G. L. Survival of primates in LD100 septic shock following steroid/antibiotic therapy. J Surg Res. 1980 Feb;28(2):151–170. doi: 10.1016/0022-4804(80)90158-4. [DOI] [PubMed] [Google Scholar]
  18. Hinshaw L. B., Beller-Todd B. K., Archer L. T., Benjamin B., Flournoy D. J., Passey R., Wilson M. F. Effectiveness of steroid/antibiotic treatment in primates administered LD100 Escherichia coli. Ann Surg. 1981 Jul;194(1):51–56. doi: 10.1097/00000658-198107000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hinshaw L. B., Emerson T. E., Jr, Chang A. C., Duerr M., Peer G., Fournel M. Study of septic shock in the non-human primate: relationship of pathophysiological response to therapy with anti-TNF antibody. Circ Shock. 1994 Dec;44(4):221–229. [PubMed] [Google Scholar]
  20. Hinshaw L. B., Tekamp-Olson P., Chang A. C., Lee P. A., Taylor F. B., Jr, Murray C. K., Peer G. T., Emerson T. E., Jr, Passey R. B., Kuo G. C. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock. 1990 Mar;30(3):279–292. [PubMed] [Google Scholar]
  21. Ischiropoulos H., Zhu L., Beckman J. S. Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys. 1992 Nov 1;298(2):446–451. doi: 10.1016/0003-9861(92)90433-w. [DOI] [PubMed] [Google Scholar]
  22. Klosterhalfen B., Hörstmann-Jungemann K., Vogel P., Flohé S., Offner F., Kirkpatrick C. J., Heinrich P. C. Time course of various inflammatory mediators during recurrent endotoxemia. Biochem Pharmacol. 1992 May 28;43(10):2103–2109. doi: 10.1016/0006-2952(92)90167-h. [DOI] [PubMed] [Google Scholar]
  23. Kreger B. E., Craven D. E., McCabe W. R. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med. 1980 Mar;68(3):344–355. doi: 10.1016/0002-9343(80)90102-3. [DOI] [PubMed] [Google Scholar]
  24. Lloyd S. S., Chang A. K., Taylor F. B., Jr, Janzen E. G., McCay P. B. Free radicals and septic shock in primates: the role of tumor necrosis factor. Free Radic Biol Med. 1993 Mar;14(3):233–242. doi: 10.1016/0891-5849(93)90020-u. [DOI] [PubMed] [Google Scholar]
  25. Maeda H., Akaike T., Yoshida M., Suga M. Multiple functions of nitric oxide in pathophysiology and microbiology: analysis by a new nitric oxide scavenger. J Leukoc Biol. 1994 Nov;56(5):588–592. doi: 10.1002/jlb.56.5.588. [DOI] [PubMed] [Google Scholar]
  26. Minnard E. A., Shou J., Naama H., Cech A., Gallagher H., Daly J. M. Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg. 1994 Feb;129(2):142–148. doi: 10.1001/archsurg.1994.01420260038004. [DOI] [PubMed] [Google Scholar]
  27. Ochoa J. B., Udekwu A. O., Billiar T. R., Curran R. D., Cerra F. B., Simmons R. L., Peitzman A. B. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg. 1991 Nov;214(5):621–626. doi: 10.1097/00000658-199111000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Rahhal S., Richter H. W. Reaction of hydroxyl radicals with the ferrous and ferric iron chelates of diethylenetriamine-N,N,N',N",N"- pentaacetate. Free Radic Res Commun. 1989;6(6):369–377. doi: 10.3109/10715768909087920. [DOI] [PubMed] [Google Scholar]
  30. Silva A. T., Bayston K. F., Cohen J. Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative shock. J Infect Dis. 1990 Aug;162(2):421–427. doi: 10.1093/infdis/162.2.421. [DOI] [PubMed] [Google Scholar]
  31. Stone R. Search for sepsis drugs goes on despite past failures. Science. 1994 Apr 15;264(5157):365–367. doi: 10.1126/science.8153620. [DOI] [PubMed] [Google Scholar]
  32. Szabó C., Wu C. C., Gross S. S., Thiemermann C., Vane J. R. Interleukin-1 contributes to the induction of nitric oxide synthase by endotoxin in vivo. Eur J Pharmacol. 1993 Nov 30;250(1):157–160. doi: 10.1016/0014-2999(93)90634-t. [DOI] [PubMed] [Google Scholar]
  33. Taylor F. B., Jr, Kosanke S., Randolph M., Emerson T., Hinshaw L. B., White G. L., Chang A. C., Peer G., Blick K. Retrospective description and experimental reconstitution of three different responses of the baboon to lethal E. coli. Circ Shock. 1994 Feb;42(2):92–103. [PubMed] [Google Scholar]
  34. Thiemermann C., Wu C. C., Szabó C., Perretti M., Vane J. R. Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. Br J Pharmacol. 1993 Sep;110(1):177–182. doi: 10.1111/j.1476-5381.1993.tb13789.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. 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]
  37. Vane J. R., Anggård E. E., Botting R. M. Regulatory functions of the vascular endothelium. N Engl J Med. 1990 Jul 5;323(1):27–36. doi: 10.1056/NEJM199007053230106. [DOI] [PubMed] [Google Scholar]
  38. Wang P., Ba Z. F., Chaudry I. H. Nitric oxide. To block or enhance its production during sepsis? Arch Surg. 1994 Nov;129(11):1137–1143. doi: 10.1001/archsurg.1994.01420350035003. [DOI] [PubMed] [Google Scholar]
  39. Wong C., Fox R., Demling R. H. Effect of hydroxyl radical scavenging on endotoxin-induced lung injury. Surgery. 1985 Mar;97(3):300–307. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES