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01.08.2006 | Experimental

DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats

verfasst von: Yan Li, Xuemei Li, Michael Haley, Yvonne Fitz, Eric Gerstenberger, Steven M. Banks, Peter Q. Eichacker, Xizhong Cui

Erschienen in: Intensive Care Medicine | Ausgabe 8/2006

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Abstract

Objective

Nonselective inhibition of nitric oxide (NO) with NO synthase antagonists decreases hypotension but worsens outcome clinically. We investigated whether iron (III) complex of diethylenetriaminepentaacetic acid [DTPA Fe(III)], a scavenger of NO as well as other oxidant mediators, has similar divergent effects in E. coli challenged rats.

Methods

Animals with venous and arterial catheters and challenged with intrabronchial or intravenous E. coli were randomized to treatment with DTPA Fe(III) in doses from 3 to 800 mg/kg or placebo. Mean blood pressure (MBP) was measured in all animals and plasma NO, cytokines, and blood and lung leukocyte and bacteria counts in animals administered intrabronchial E. coli and DTPA Fe(III) 50 mg/kg or placebo. Animals received antibiotics and were observed 168 h.

Results

Independent of drug regimen or infection site, compared to placebo, DTPA Fe(III) increased MBP although this was greater with high vs. lower doses. Despite increased MBP, DTPA Fe(III) worsened the hazards ratio of survival . At 6 and 24 h DTPA Fe(III) decreased NO but not significantly and decreased four cytokines (tumor necrosis factor-α, interleukins 1 and 10, and macrophage inflammatory protein 3α) and lung lavage neutrophils. From 6 to 24 h DTPA Fe(III) increased blood bacteria.

Conclusions

DTPA Fe(III) while increasing blood pressure has the potential to worsen outcome in sepsis. Further preclinical testing is required before this agent is applied clinically.

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Cobb JP, Danner RL (1996) Nitric oxide and septic shock. JAMA 275:1192–1196PubMedCrossRef

Kengatharan KM, De Kimpe SJ, Thiemermann C (1996) Role of nitric oxide in the circulatory failure and organ injury in a rodent model of gram-positive shock. Br J Pharmacol 119:1411–1421PubMed

Farias NC, Borelli-Montigny GL, Fauaz G, Feres T, Borges AC, Paiva TB (2002) Different mechanism of LPS-induced vasodilation in resistance and conductance arteries from SHR and normotensive rats. Br J Pharmacol 137:213–220PubMedCrossRef

Thiemermann C, Vane J (1990) Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol 182:591–595PubMedCrossRef

Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF (1990) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172:1132–1138PubMedCrossRef

Molina L, Studenberg S, Wolberg G, Kazmierski W, Wilson J, Tadepalli A, Chang AC, Kosanke S, Hinshaw L (1996) Efficacy of treatment with the iron (III) complex of diethylenetriamine pentaacetic acid in mice and primates inoculated with live lethal dose 100 Escherichia coli. J Clin Invest 98:192–198PubMedCrossRef

Cobb JP, Natanson C, Hoffman WD, Lodato RF, Banks S, Koev CA, Solomon MA, Elin RJ, Hosseini JM, Danner RL (1992) N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 176:1175–1182PubMedCrossRef

Cobb JP, Natanson C, Quezado ZM, Hoffman WD, Koev CA, Banks S, Correa R, Levi R, Elin RJ, Hosseini JM, Danner RL (1995) Differential hemodynamic effects of L-NMMA in endotoxemic and normal dogs. Am J Physiol 268:H1634–1642PubMed

Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32:21–30PubMedCrossRef

10.

Wright CE, Rees DD, Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26:48–57PubMedCrossRef

11.

Babu BR, Griffith OW (1998) Design of isoform-selective inhibitors of nitric oxide synthase. Curr Opin Chem Biol 2:491–500PubMedCrossRef

12.

Kazmierski WM, Wolberg G, Wilson JG, Smith SR, Williams DS, Thorp HH, Molina L (1996) Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock. Proc Natl Acad Sci U S A 93:9138–9141PubMedCrossRef

13.

Li Y, Molina L, Solomon S, Fitz Y, Danner RL, Natanson C, Eichacker PQ, Cui X (2004) Iron (III) complex of diethylenetraimine pentaacetic acid [DTPA Fe(III)] decreased nitrate/nitrite levels and increased blood pressure but not survival during E. coli sepsis in rats. Am J Respir Crit Care Med 169:A632

14.

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310PubMedCrossRef

15.

Freeman BD, Correa R, Karzai W, Natanson C, Patterson M, Banks S, Fitz Y, Danner RL, Wilson L, Eichacker PQ (1996) Controlled trials of rG-CSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats. J Appl Physiol 80:2066–2076PubMed

16.

Yang BK, Vivas EX, Reiter CD, Gladwin MT (2003) Methodologies for the sensitive and specific measurement of S-nitrosothiols, iron-nitrosyls, and nitrite in biological samples. Free Radic Res 37:1–10PubMedCrossRef

17.

Cui X, Parent C, Macarthur H, Ochs SD, Gerstenberg E, Solomon S, Fitz Y, Danner RL, Banks SM, Natanson C, Salvemini D, Eichacker PQ (2004) Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model. J Appl Physiol 97:1349–1357PubMedCrossRef

18.

Rahhal S, Richter HW (1989) Reaction of hydroxyl radicals with the ferrous and ferric iron chelates of diethylenetriamine-N,N,N',N",N"- pentaacetate. Free Radic Res Commun 6:369–377PubMedCrossRef

19.

Pasternack R, Halliwell B (1979) Superoxide dismutase activities of an iron porphyrin and other iron complexes. J Am Chem Soc 101:1026–1031CrossRef

20.

Albuszies G, Bruckner UB (2003) Antioxidant therapy in sepsis. Intensive Care Med 29:1632–1636PubMedCrossRef

21.

Macarthur H, Westfall TC, Riley DP, Misko TP, Salvemini D (2000) Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A 97:9753–9758PubMedCrossRef

22.

Macarthur H, Couri DM, Wilken GH, Westfall TC, Lechner AJ, Matuschak GM, Chen Z, Salvemini D (2003) Modulation of serum cytokine levels by a novel superoxide dismutase mimetic, M40401, in an Escherichia coli model of septic shock: correlation with preserved circulating catecholamines. Crit Care Med 31:237–245PubMedCrossRef

23.

Dinarello CA (1997) Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112:321S-329SCrossRef

24.

Bogdan C, Rollinghoff M, Diefenbach A (2000) Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr Opin Immunol 12:64–76PubMedCrossRef

25.

Vazquez-Torres A, Jones-Carson J, Mastroeni P, Ischiropoulos H, Fang FC (2000) Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro. J Exp Med 192:227–236PubMedCrossRef

26.

Mastroeni P, Vazquez-Torres A, Fang FC, Xu Y, Khan S, Hormaeche CE, Dougan G (2000) Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo. J Exp Med 192:227–236PubMedCrossRef

27.

Darrah PA, Hondalus MK, Chen Q, Ischiropoulos H, Mosser DM (2000) Cooperation between reactive oxygen and nitrogen intermediates in killing of Rhodococcus equi by activated macrophages. Infect Immun 68:3587–3593PubMedCrossRef

28.

Miyagi K, Kawakami K, Saito A (1997) Role of reactive nitrogen and oxygen intermediates in gamma interferon-stimulated murine macrophage bactericidal activity against Burkholderia pseudomallei. Infect Immun 65:4108–4113PubMed

29.

Mastroeni P, Skepper JN, Hormaeche CE (1995) Effect of anti-tumor necrosis factor alpha antibodies on histopathology of primary Salmonella infections. Infect Immun 63:3674–3682PubMed

30.

Bagby GJ, Plessala KJ, Wilson LA, Thompson JJ, Nelson S (1991) Divergent efficacy of antibody to TNF in intravascular and peritonitis models of sepsis. J Infect Dis 163:83–88PubMed

31.

Echtenacher B, Falk W, Mannel DN, Krammer PH (1990) Requirement of endogenous tumor necrosis factor/cachetin for recovery from experimental peritonitis. J Immunol 145:3762–3766PubMed

32.

Haley M, Parent C, Cui X, Kalil A, Fitz Y, Correa-Araujo R, Natanson C, Danner RL, Banks SM, Eichacker PQ (2005) Neutrophil inhibition with L-selectin directed mAb improves or worsens survival dependent upon the route but not severity of infection in a rat sepsis model. J Appl Physiol 98:2155–2162PubMedCrossRef

33.

Kim YM, Hong SJ, Billiar TR, Simmons RL (1996) Counterprotective effect of erythrocytes in experimental bacterial peritonitis is due to scavenging of nitric oxide and reactive oxygen intermediates. Infect Immun 64:3074–3080PubMed

34.

Umezawa K, Akaike T, Fujii S, Suga M, Setoguchi K, Ozawa A, Maeda H (1997) Induction of nitric oxide synthesis and xanthine oxidase and their roles in the antimicrobial mechanism against Salmonella typhimurium infection in mice. Infect Immun 65:2932–2940PubMed

35.

Cohen RI, Shapir Y, Chen L, Scharf SM (1998) Right ventricular overload causes the decrease in cardiac output after nitric oxide synthesis inhibition in endotoxemia. Crit Care Med 26:738–747PubMedCrossRef

36.

Henderson JL, Statman R, Cunningham JN, Cheng W, Damiani P, Siconolfi A, Horovitz JH (1994) The effects of nitric oxide inhibition on regional hemodynamics during hyperdynamic endotoxemia. Arch Surg 129:1271–1274PubMed

37.

Dahm PL, Thorne J, Myhre E, Grins E, Martensson L, Blomquist S (1999) Intestinal and hepatic perfusion and metabolism in hypodynamic endotoxic shock. Effects of nitric oxide synthase inhibition. Acta Anaesthesiol Scand 43:56–63PubMedCrossRef

38.

Eichacker PQ, Parent C, Kalil A, Esposito C, Cui X, Banks SM, Gerstenberger EP, Fitz Y, Danner RL, Natanson C (2002) Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 166:1197–1205PubMedCrossRef

Titel: DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats
verfasst von: Yan Li
Xuemei Li
Michael Haley
Yvonne Fitz
Eric Gerstenberger
Steven M. Banks
Peter Q. Eichacker
Xizhong Cui
Publikationsdatum: 01.08.2006
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 8/2006
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-006-0234-2

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DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats