The effect of peroxisome proliferator-activated receptor-  ligands on in vitro and in vivo models of COPD

Abstract

Peroxisome proliferator-activated receptor (PPAR)-c is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-c ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD).PPAR-c protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-c ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-c ligands in a subchronic tobacco smoke model in mice were investigated.PPAR-c protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-c ligands reduced tumour necrosis factor-a and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation.We show biological actions of PPAR-c agonists on corticosteroid-resistant disease, tobacco smokeinduced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils.@ERSpublications Biological actions of a PPAR-c agonist shown in COPD-relevant models may affect progression and side-effects in patients

Down-regulated Peroxisome Proliferator-activated Receptor γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD)

“…Other previous investigations have shown that PPAR␥ activation can attenuate inflammation either in animal models of COPD or following CSE exposure in vitro, but have not addressed the signaling pathways we investigated. Both the thiazolidinedione pioglitazone (29) and the endogenous PPAR␥ agonist 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) (30) have proven effective in the LPS-induced model of COPD, while both Rosi and pioglitazone were effective in a smoke-induced model (28). In vitro, Lee et al (31) attributed the ability of Rosi to inhibit CSE-induced TNF-␣ and mucin production in H292 cells to up-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), with consequent down-regulation of the Akt signaling pathway.…”

An investigation into the effect of erythromycin on Pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis

“…However, previous studies have shown a strong correlation between PPARγ gene expression and protein activity suggesting that this method is acceptable [164]. Previous studies assessing airway PPARγ expression in association with disease states have also arrived at similar conclusions [114,115], meaning that this study is consistent with the reported literature of a down regulation of PPARγ in inflammatory airways diseases. Another limitation could be the baseline differences between the healthy control and the bronchiectasis group.…”

“…Inhibition of PPARγ has been shown to produce a pro-inflammatory phenotype by interfering with its inhibitory action on the target genes of NFκB [113]. PPARγ production has been shown to be down-regulated in inflammatory airways diseases, including COPD [114] and CF [115], suggesting its suppression is involved in the underlying pathology. In vitro studies have demonstrated that the presence of P. aeruginosa AHLs suppress expression of PPARγ [111,115].…”

“…PPARγ production has been shown to be down-regulated in inflammatory airways diseases, including COPD [114] and cystic fibrosis [115], suggesting its involvement in the underlying pathology. The mechanism by which PPARγ production is suppressed is not known.…”

Addressing corticosteroid insensitivity in adults with asthma

“…Peroxisome proliferator-activated receptor-γ (PPARγ) agonists are members of the nuclear receptor family that exert in pre-clinical studies anti-inflammatory effects potentially relevant to the treatment of airway diseases and to restoring corticosteroid sensitivity [141,142]. A proof of concept study using the oral PPARγ agonist rosiglitazone demonstrated bronchodilator effects in mild to moderate smokers with asthma who had non-eosinophilic inflammation [143].…”