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

Abstract

Objective Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor. Ciglitazone a PPARγ 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 following 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 (MAP) of 50 mmHg. At 3 hours after hemorrhage, rats were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, animals received ciglitazone (10mg/kg) or vehicle intraperitoneally. Heart rate and MAP were measured throughout the experiment. Plasma and lung tissue were collected for analysis up to 3 hours after resuscitation. Measurements and Main results Ciglitazone treatment ameliorated MAP, reduced lung injury, significantly blunted lung neutrophil infiltration and lowered plasma interleukin -6 (IL-6), interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) levels. In a time course analysis, vehicle-treated rats had a significant increase in nuclear factor-κB (NF-κB) DNA binding, which was preceded by increased inhibitor κB (IκB) protein kinase (IKK) activity and IκBα degradation in the lung. Treatment with ciglitazone significantly reduced IKK activity and IκBα degradation and completely inhibited NF-κB DNA binding. This reduction of IKK activity afforded by ciglitazone appeared to be a consequence of a physical interaction between PPARγ and IKK. Conclusion Ciglitazone ameliorates the inflammatory response and may reduce lung injury following hemorrhagic shock. These protective effects appear to be mediated through inhibition of the IKK/NF-κB pathway.

Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

“…Consistent with these previous findings, in the present study we have demonstrated that ciglitazone reduced liver neutrophil infiltration in both age groups. Similar beneficial effects of PPAR␥ ligands on tissue leukosequestration have been found in hemorrhagic shock in experimental young animals (4,39). Thus the protective effect of PPAR␥ ligands may be attributed to control of inflammation.…”

“…In this regard, natural (cyclopentenone prostaglandins) and synthetic PPAR␥ ligands (thiazolidinediones) have been reported to exert beneficial effects in hemorrhagic shock in young experimental animals (1,5). We have also demonstrated that pharmacological activation of PPAR␥ reduces the systemic inflammatory response and lung injury secondary to severe hemorrhage (4,39) and preserves organ structure and function in hepatic ischemia and reperfusion injury in young rats (19). To further support the role of PPAR␥ in inflammation, several studies including ours have reported that its expression and function may be altered by cytotoxic mediators.…”

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

“…Thus, it is not surprising that much attention has focused on the development of drugs and tools that are able to target this transcription factor (8)(9)(10)(11)24). However, the effects of the inhibition of IKK in the MOF induced by HS have not been investigated.…”

“…There is indirect evidence that agents that prevent the activation of NF-κB (for example, calpain inhibitor I) are also of benefit in HS (14). Other examples include ciglitazone (a peroxisome proliferator-activated receptor [PPAR]-γ ligand) and eritoran (a toll-like receptor 4 [TLR4] antagonist), which attenuate organ damage in HS through the indirect inhibition of NF-κB (8,10). However, the effects of the inhibition of IKK in HS have yet to be investigated.…”

“…There is now growing evidence that inhibition of the activation of NF-κB may reduce organ injury and dysfunction in septic and hemorrhagic shock (HS) (8)(9)(10)(11). The inhibition of IKK complex by IKK16 and the consequent prevention of the activation of NF-κB reduce the cardiac dysfunction, liver injury and renal dysfunction caused by sepsis (12) and ventilation-induced lung injury (13).…”