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Down-regulated peroxisome proliferator-activated receptor ? (PPAR?) in lung epithelial cells promotes a PPAR? agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor ? (PPAR?), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPAR? was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-?B (NF-?B) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPAR? and activated NF-?B. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-?) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPAR? agonists strongly up-regulated PPAR? expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-?B by inhibiting the I?B kinase pathway and by promoting direct inhibitory binding of PPAR? to NF-?B. In contrast, PPAR? knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPAR?. The results imply that down-regulation of pulmonary epithelial PPAR? by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPAR? agonists may be useful for COPD treatment.

SUBMITTER: Lakshmi SP

PROVIDER: S-EPMC3945305 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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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).

Lakshmi Sowmya P SP Reddy Aravind T AT Zhang Yingze Y Sciurba Frank C FC Mallampalli Rama K RK Duncan Steven R SR Reddy Raju C RC

The Journal of biological chemistry 20131224 10

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated in ...[more]

PMID: 24368768

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Project description:Ascites (serous fluid accumulation in the abdominal cavity) has been observed worldwide in fast growing broilers. Pulmonary vascular remodeling is an important pathological feature of broiler ascites syndrome. Peroxisome proliferators-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) are expressed in pulmonary vascular endothelial cells and vascular smooth muscle cells (VSMC) where they participate in the regulation of normal pulmonary vascular function. The objective of the present study was to investigate the effects of omega-3 fatty acids (found in fish oil) and pioglitazone (PIO) as natural and synthetic PPARγ ligands supplementation on PPARγ and PGC-1α expression in the prevention of pulmonary arterial hypertension (PAH) syndrome in broiler chickens. The experiment was conducted with 4 treatment groups: 1) negative control, normal temperature conditions with basal diet; 2) positive control, low-temperature conditions with basal diet; 3) positive control + 10 mg PIO/kg of weight/d and 4) positive control + 1% FO. Each treatment had 5 replicates. Ascites heart index (RV/TV) was significantly (P < 0.05) reduced in chickens receiving FO (0.20) and PIO (0.21) compared to the positive control group (0.26). The addition of PIO in broilers under cold-induced ascites significantly increased the expression of PPARγ (9.44) and PGC-1α (5.81) genes in lung tissue compared to the negative control group (1.03, P < 0.05). Proliferative indexes of VSMC in pulmonary arteries such as PMT, PIT, and percentage wall thickness were significantly elevated in positive control group, indicating that pulmonary vascular remodeling occurred following VSMC proliferation in ascites. The vessel internal diameter was increased in FO and PIO groups. Based on these results, activation and expression of PPARγ and PGC-1α genes as a critical regulator of pulmonary artery smooth muscle cell using ligands, especially PIO, can be effective in reducing the incidence of PAH in broiler chickens.

Dataset Information

Down-regulated peroxisome proliferator-activated receptor ? (PPAR?) in lung epithelial cells promotes a PPAR? agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

Publications

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).

Similar Datasets

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