Ciglitazone ameliorates lung inflammation by modulating the inhibitor κB protein kinase/nuclear factor-κB pathway after hemorrhagic shock

Objective: Peroxisome proliferator-activated receptor-gamma is a ligand-activated transcription factor. Ciglitazone, a peroxisome pro liferator-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-kappa B DNA binding, which was preceded by increased inhibitor kappa B protein kinase activity and inhibitor kappa B alpha degradation in the lung. Treatment with ciglitazone significantly reduced inhibitor kappa B protein kinase activity and inhibitor kappa B alpha. degradation and completely inhibited nuclear factor-kappa B DNA binding. This reduction of inhibitor kappa B protein kinase activity afforded by ciglitazone appeared to be a consequence of a physical interaction between peroxisome proliferator-activated receptor-gamma and increased inhibitor kappa B 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 kappa B protein kinase/nuclear factor-kappa B pathway.