Ranjit S. Chima, P. Hake, G. Piraino
Oct 1, 2008
Citations
1
Influential Citations
46
Citations
Quality indicators
Journal
Critical Care Medicine
Abstract
Objective:Peroxisome proliferator-activated receptor-γ is a ligand-activated transcription factor. Ciglitazone, a peroxisome proliferator-activated receptor-γ 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-&kgr;B DNA binding, which was preceded by increased inhibitor &kgr;B protein kinase activity and inhibitor &kgr;Bα degradation in the lung. Treatment with ciglitazone significantly reduced inhibitor &kgr;B protein kinase activity and inhibitor &kgr;Bα degradation and completely inhibited nuclear factor-&kgr;B DNA binding. This reduction of inhibitor &kgr;B protein kinase activity afforded by ciglitazone appeared to be a consequence of a physical interaction between peroxisome proliferator-activated receptor-γ and increased inhibitor &kgr;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 &kgr;B protein kinase/nuclear factor-&kgr;B pathway.