Original Article Ciglitazone, a novel inhibitor of Lung Apoptosis following Hemorrhagic Shock
Ranjit S. Chima, Paul W. Hake, Giovanna Piraino, Prajakta Mangeshkar, Michael O’Connor, Basilia Zingarelli
Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
Received December 2, 2009; accepted December 10, 2009; available online January 1, 2010
Abstract: Apoptosis or programmed cell death has been demonstrated to play a role in the development of lung injury following hemorrhagic shock. A major pathway modulating the apoptotic response is the phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) pathway. Ciglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) ligand has previously been shown to attenuate lung inflammation following hemorrhagic shock. In vivo similar ligands have demonstrated anti-apoptotic effects with a reduction in organ injury in models of acute illness. In this study we examined the effect of ciglitazone on apoptosis and PI3K/Akt signaling in the lung following severe hemorrhage and resuscitation. Hemorrhagic shock was induced in male Wistar rats by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3h at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, groups of animals received ciglitazone (10mg/kg) or DMSO intraperitoneally. Vehicle-treated rats had increased lung apoptosis following hemorrhage and resuscitation by Tunel staining. This was associated with increased activity of caspase-3. Ciglitazone treatment reduced lung apoptosis with a significant reduction in caspase-3 activity. This was associated with increased phosphorylation of the pro-survival kinase Akt. Thus, our data suggest that ciglitazone, a PPARγ ligand, promotes cell survival in the lung following hemorrhagic shock. (IJCEM912002).
Address all correspondence to: Ranjit S. Chima M.D. Division of Critical Care Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati, OH 45229 Tel: (513) 636-4259 Fax: (513) 636-4267 E-mail: email@example.com