Emerging PPARγ-Independent Role of PPARγLigands in Lung Diseases

Peroxisome proliferator activated receptor (PPAR)- γ is a nuclear hormone receptor that is activated by multiple agonists including thiazolidinediones, prostaglandins, and synthetic oleanolic acids. Many PPAR γ ligands are under investigation as potential therapies for human diseases. These ligands modulate multiple cellular pathways via both PPAR γ -dependent and PPAR γ -independent mechanisms. Here, we review the role of PPAR γ and PPAR γ ligands in lung disease, with emphasis on PPAR γ -independent effects. PPAR γ ligands show great promise in moderating lung inflammation, as antiproliferative agents in combination to enhance standard chemotherapy in lung cancer and as treatments for pulmonary fibrosis, a progressive fatal disease with no effective therapy. Some of these effects occur when PPAR γ is pharmaceutically antagonized or genetically PPAR γ and are thus independent of classical PPAR γ -dependent transcriptional control. Many PPAR γ ligands demonstrate direct binding to transcription factors and other proteins, altering their function and contributing to PPAR γ -independent inhibition of disease phenotypes. These PPAR γ -independent mechanisms are of significant interest because they suggest new therapeutic uses for currently approved drugs and because they can be used as probes to identify novel proteins and pathways involved in the pathogenesis or treatment of disease, which can then be targeted for further investigation and drug development.