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Vol. 61, Issue 5, 953-963, May 2002
B Pathway,
Ameliorates Cardiovascular Derangement and Outcome in Endotoxic Shock
in Rodents
Children's Hospital Medical Center, Division of Critical Care
Medicine, Cincinnati, Ohio
Parthenolide is a sesquiterpene lactone used in folk medicine for its
anti-inflammatory activity. Recent in vitro studies have shown that
this compound inhibits the nuclear factor (NF)-
B pathway. This study
examines the effect of parthenolide in endotoxic shock in rodents.
Endotoxic shock was induced by administration of Escherichia
coli endotoxin in rats. Three groups of rats received parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before endotoxin; another
group received parthenolide (1 mg/kg) 3 h after endotoxin. In
vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to
norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed
positive staining for nitrotyrosine, poly(ADP-ribose) synthetase (PARS)
and apoptosis, whereas Northern blot analysis showed increased mRNA
expression of inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma nitrate/nitrite were also found. Elevated lung levels of myeloperoxidase activity were indicative of
infiltration of neutrophils. These inflammatory events were preceded by
cytosolic degradation of inhibitor B
(IB) and activation of
nuclear NF-B in the lung. In vivo pretreatment and post-treatment
with parthenolide improved the hemodynamic profile and reduced plasma
nitrate/nitrite and lung neutrophil infiltration in a dose-dependent
fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated.
Treatment with parthenolide also abolished nitrotyrosine formation,
PARS expression, and apoptosis and reduced iNOS mRNA content in
thoracic aortas. DNA binding of NF-B was inhibited by parthenolide
in the lung, whereas degradation of IB was unchanged. In a
separate set of experiments, pretreatment or post-treatment with
parthenolide significantly improved survival in mice challenged with
endotoxin. We conclude that parthenolide exerts beneficial effects
during endotoxic shock through inhibition of NF-B.
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