Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis

Francisco Garcia Soriano, Clara Batista Lorigados, Pal Pacher, Csaba Szabo

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)560-566
Number of pages7
JournalShock
Volume35
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Peroxynitrous Acid
Endotoxemia
Sepsis
Liver
Blood Urea Nitrogen
Nitrites
Malondialdehyde
Alanine Transaminase
Punctures
Superoxides
Nitrates
Peroxidase
Nitric Oxide
Cell Death
Pharmacology
Lung
Porphyrins
Wounds and Injuries
Lung Injury
Septic Shock

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

Cite this

Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. / Soriano, Francisco Garcia; Lorigados, Clara Batista; Pacher, Pal; Szabo, Csaba.

In: Shock, Vol. 35, No. 6, 06.2011, p. 560-566.

Research output: Contribution to journalArticle

Soriano, Francisco Garcia ; Lorigados, Clara Batista ; Pacher, Pal ; Szabo, Csaba. / Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. In: Shock. 2011 ; Vol. 35, No. 6. pp. 560-566.
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