Role of peroxisome-proliferator activated receptors in sepsis and trauma
We are investigating the role of the nuclear hormone receptors, peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs) in experimental models of sepsis and trauma. We have discovered that these important receptors, which normally control lipid and glucose metabolism, are also beneficial factors in combating infections and inflammation during sepsis and trauma. A major focus of investigation is to understand how these receptors interact with pathways that facilitate the progression of inflammation and cell death, such as the nuclear factor- κΒ and activator protein-1, and ultimately lead to organ damage. Also, we are investigating the molecular mechanisms that control the function of these receptors, such as the recruitment of ligands, co-activators and co-repressors.
To support the clinical relevance of our data, in collaboration with
laboratories we have observed that the expression and function of PPARγ is altered in peripheral blood mononuclear cells and correlates with severity of sepsis in critically ill children. These findings, together with the basic science discoveries, hold the promise to identify new therapeutic targets to treat sepsis and improve child health. Since the synthetic ligands for PPARγ, the thiazolidinediones, are used clinically as anti-diabetic drugs, we are taking further steps to explore the possibility to use this class of compounds in pediatric patients with sepsis and we have started to study safety of pioglitazone treatment in a prospective randomized phase I clinical trial.
|The nuclear hormone receptors, PPARγ, PPARα, PPARδ and LXRα regulate lipid and glucose metabolism in liver, muscle and adipose tissue. These receptors are also expressed in other cell types, including epithelial, endothelial, immuno-regulatory, and parenchyma cells of several organs, where they can control immunity and inflammation by regulating transcription or transrepression of specific genes. The function of these receptors depends on the recruitment of specific ligands and other nuclear co-factors. The thiazolidinediones are synthetic PPARγ ligands and approved by the Food and Drug Administration for type II diabetes treatment.