Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARg regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of genes involved in lipid biosynthesis and glucose metabolism. However, more recently PPARg, PPARa and PPARb/d agonists have been demonstrated to exhibit anti-inflammatory and immunomodulatory properties thus opening up new avenues for research. The actions of PPARg and PPARa activation are thought to be due to their ability to down regulate pro-inflammatory gene expression and inflammatory cell functions, and as such makes them an attractive target for novel drug intervention. Interestingly, PPARb/d has been shown to be involved in wound healing, angiogenesis, lipid metabolism and thrombosis. In this review we will focus on the data describing the beneficial effects of these ligands in the airway and in the pulmonary vasculature and in vivo in animal models of allergic and occupational asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. A clinical trial is underway to examine the effect of rosiglitazone in asthma patients and the outcome of this trial is awaited with much anticipation. In conclusion, PPARs are novel targets for lung disease and continued work with these ligands may result in a potential new treatment for chronic inflammatory lung diseases.

Chronic exposure to perfluorinated compounds: Impact on airway hyperresponsiveness and inflammation

“…PFOS have higher affinity to PPAR␥ than PFOA, and PFOA have higher affinity and activation of PPAR␣ than PFOS (16). PPAR␥ agonist are known to have anti-inflammatory properties and regulate cytokine secretion by airway smooth muscle (4,18). In this regard, future study using a murine PPAR knockout model is highly desirable to elucidate the mechanism of AHR observed in this study.…”

Emerging anti-inflammatory strategies for COPD

“…Originally identified for their role in lipid and glucose regulation, PPARs have more recently been implicated in the regulation of other phenomena, including inflammation [105]. In particular, PPARs have been demonstrated to be involved in the modulation of NF-kB transcriptional activity [106].…”

The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

“…20 In sham-operated animals, treatment with GW0742 induced significant changes (increase or decrease) in 59 genes, with 36 being increased and 23 being decreased. Using a cutoff of genes altered ≥1.5-fold resulted in a list of 20 genes being significantly changed in right heart tissue of sham-operated mice treated with GW0742; 14 genes were increased, and 6 were decreased.…”

“…Indeed, the AMP kinase activator AICAR inhibits cardiac fibroblast proliferation 32,33 and protects against myocardial injury after ischemia reperfusion. 33 PPARβ/δ mediates its effects via genomic 34 and nongenomic 20,35 pathways. In the current study, we analyzed genomic influences by monitoring global gene induction Note: Animals underwent a sham operation and after several days were orally dosed with vehicle or GW0742 (30 mg/kg).…”