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.