Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis.
Excessive free-radical production due to various bacterial components released during bacterial infection has been linked to cell death and tissue injury. Peroxynitrite is a highly reactive oxidant produced by the combination of nitric oxide (NO) and superoxide anion, which has been implicated in cell death and tissue injury in various forms of critical illness. Pharmacological decomposition of peroxynitrite may represent a potential therapeutic approach in diseases associated with the overproduction of NO and superoxide. In the present study, we tested the effect of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Mice were injected i.p. with LPS 40 mg/kg with or without FP15 [Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin] (0.1, 0.3, 1, 3, or 10 mg/kg per hour). Mice were killed 12 h later, followed by the harvesting of samples from the lung, liver, and gut for malondialdehyde and myeloperoxidase measurements. In other subsets of animals, blood samples were obtained by cardiac puncture at 1.5, 4, and 8 h after LPS administration for cytokine (TNF-α, IL-1β, and IL-10), nitrite/nitrate, alanine aminotransferase, and blood urea nitrogen measurements. Endotoxemic animals showed an increase in survival from 25% to 80% at the FP15 doses of 0.3 and 1 mg/kg per hour. The same dose of FP15 had no effect on plasma levels of nitrite/nitrate. There was a reduction in liver and lung malondialdehyde in the endotoxemic animals pretreated with FP15, as well as in hepatic myeloperoxidase and biochemical markers of liver and kidney damage (alanine aminotransferase and blood urea nitrogen). In a bacterial model of sepsis induced by cecal ligation and puncture, FP15 treatment (0.3 mg/kg per day) significantly protected against mortality. The current data support the view that peroxynitrite is a critical factor mediating liver, gut, and lung injury in endotoxemia and septic shock: its pharmacological neutralization may be of therapeutic benefit.
Laboratório da Disciplina de Emergências Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Francisco Garcia
FG
Soriano
Clara Batista
CB
Lorigados
Pal
P
Pacher
Csaba
C
Szabó
D000818:Animals; D019446:Endotoxemia / Q000188:drug therapy*; D008070:Lipopolysaccharides; D008315:Malondialdehyde / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000009:adverse effects / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*
C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D009566:Nitrates; D009573:Nitrites; D030421:Peroxynitrous Acid; D008315:Malondialdehyde; D009195:Peroxidase
Clin Infect Dis. 2002 Apr 15;34(8):1084-93
11914997
Crit Care Med. 2002 May;30(5):1071-82
12006805
J Biol Chem. 2005 Oct 14;280(41):34878-87
16079150
Crit Care Med. 2010 May;38(5):1276-83
20308885
Shock. 2010 Sep;34 Suppl 1:4-14
20523270
Crit Care Med. 2006 Apr;34(4):1073-9
16484919
Crit Care Med. 2004 May;32(5 Suppl):S313-9
15118537
Mech Ageing Dev. 2007 Feb;128(2):173-81
17116320
Mol Med. 2002 Oct;8(10):581-90
12477968
Am J Physiol Lung Cell Mol Physiol. 2010 Mar;298(3):L348-60
20034962
Nat Rev Drug Discov. 2007 Aug;6(8):662-80
17667957
Circulation. 2003 Feb 18;107(6):896-904
12591762
J Heart Lung Transplant. 2003 Jul;22(7):784-93
12873547
Science. 1999 May 21;284(5418):1313-8
10334979
J Mol Cell Cardiol. 1992 Sep;24(9):1021-30
1433318
Shock. 2011 Feb;35(2):148-55
20577150
Expert Opin Investig Drugs. 2000 Jul;9(7):1651-63
11060768
Free Radic Biol Med. 1994 Feb;16(2):195-200
8005514
Mol Med. 2002 Oct;8(10):571-80
12477967
Mediators Inflamm. 2010;2010:568396
20396414
Shock. 2002 Apr;17(4):286-92
11954828
Dose Response. 2008;6(3):223-38
18846257
N Engl J Med. 2003 Apr 17;348(16):1546-54
12700374
J Pharmacol Exp Ther. 2009 Jan;328(1):152-64
18927353
Pharmacol Rev. 2001 Mar;53(1):135-59
11171943
Free Radic Biol Med. 1990;9(6):473-8
2079227
Nat Rev Drug Discov. 2005 May;4(5):421-40
15864271
Biochem Biophys Res Commun. 2008 Dec 19;377(3):786-91
18951875
J Biol Chem. 2010 May 21;285(21):15746-52
20299457
Br J Pharmacol. 1999 Jun;127(3):685-92
10401559
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1645-55
17911342
Neurosci Lett. 2006 Jul 3;401(3):236-41
16631306
Crit Care. 2010;14(4):R129
20602787
Physiol Rev. 2007 Jan;87(1):315-424
17237348
Curr Pharm Des. 2009;15(16):1918-35
19519432
Crit Care Med. 2000 Jun;28(6):1953-61
10890647
Annu Rev Pharmacol Toxicol. 1993;33:71-90
8494355
J Pharmacol Exp Ther. 2006 Oct;319(1):73-81
16815867
Ann Thorac Surg. 2002 Oct;74(4):1201-7
12400769
Free Radic Res. 2009 Jul;43(7):631-45
19418318
Kidney Int. 2000 Aug;58(2):658-73
10916089
Surg Infect (Larchmt). 2010 Jun;11(3):275-81
20524900
FEBS Lett. 1995 Sep 25;372(2-3):229-32
7556674
Am J Pathol. 2008 Jul;173(1):2-13
18535182