Experimental study.
SETTING: University laboratory.
SUBJECTS: Male CD mice.
INTERVENTIONS: We investigated the effects of
rosiglitazone (3 mg/kg) on the development of nonseptic
shock caused by
zymosan (500 mg/kg, administered intraperitoneally as a
suspension in saline) in mice.
MEASUREMENTS AND MAIN RESULTS: Organ failure and systemic
inflammation in rats were assessed 18 hrs after administration of
zymosan and/or
rosiglitazone and monitored for 12 days (for loss of
body weight and mortality rate). Treatment of mice with
rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after
zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by
zymosan.
Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by
zymosan as well as the increase in
myeloperoxidase activity and
malondialdehyde concentrations caused by
zymosan in the lung and intestine. Immunohistochemical analysis for
inducible nitric oxide synthase,
nitrotyrosine, and
poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from
zymosan-treated mice. The degree of staining for
nitrotyrosine,
inducible nitric oxide synthase, and
poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from
zymosan-treated mice that received
rosiglitazone. To elucidate whether the protective effects of
rosiglitazone are related to activation of the
PPAR-gamma receptor, we also investigated the effect of a
PPAR-gamma antagonist, GW 9662, on the protective effects of
rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with
rosiglitazone) significantly antagonized the effect of the
PPAR-gamma agonist and thus abolished the protective effect.
CONCLUSIONS: