Ciglitazone ameliorates lung inflammation by modulating the inhibitor kappaB protein kinaseuclear factor-kappaB pathway after hemorrhagic shock.

摘要

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma is a ligand-activated transcription factor. Ciglitazone, a peroxisome proliferator-activated receptor-gamma ligand, has been shown to provide beneficial effects in experimental models of sepsis and ischemia/reperfusion injury. We investigated the effects of ciglitazone on lung inflammation after severe hemorrhage. DESIGN: Prospective, laboratory study, rodent model of hemorrhagic shock. SETTING: University hospital laboratory. SUBJECTS: Male rats. INTERVENTIONS: Hemorrhagic shock was induced by withdrawing blood to a mean arterial pressure of 50 mm Hg. At 3 hrs after hemorrhage, rats were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, animals received ciglitazone (10 mg/kg) or vehicle intraperitoneally. Heart rate and mean arterial pressure were measured throughout the experiment. Plasma and lung tissue were collected for analysis up to 3 hrs after resuscitation. MEASUREMENTS AND MAIN RESULTS: Ciglitazone treatment ameliorated mean arterial pressure, reduced lung injury, significantly blunted lung neutrophil infiltration, and lowered plasma interleukin-6, interleukin-10, and monocyte chemoattractant protein-1 levels. In a time course analysis, vehicle-treated rats had a significant increase in nuclear factor-kappaB DNA binding, which was preceded by increased inhibitor kappaB protein kinase activity and inhibitor kappaB alpha degradation in the lung. Treatment with ciglitazone significantly reduced inhibitor kappaB protein kinase activity and inhibitor kappaB alpha degradation and completely inhibited nuclear factor-kappaB DNA binding. This reduction of inhibitor kappaB protein kinase activity afforded by ciglitazone appeared to be a consequence of a physical interaction between peroxisome proliferator-activated receptor-gamma and increased inhibitor kappaB protein kinase. CONCLUSION: Ciglitazone ameliorates the inflammatory response and may reduce lung injury after hemorrhagic shock.These protective effects appear to be mediated through inhibition of the inhibitor kappaB protein kinaseuclear factor-kappaB pathway.