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Diminished peroxisome proliferator-activated receptor (PPAR) regulation as a potential mechanism for the persistent inflammation in chronic obstructive pulmonary disease

ELEGI/Colt Research Laboratories, MRC/University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, UK

CORRESPONDENCE: Ellen M. Drost, ELEGI Colt Laboratory, University of Edinburgh Centre for Inflammation Research, QMRI, Edinburgh, UK

Persistent inflammation is the main pathological process that underlies COPD. Understanding this inflammatory response is a key focus of COPD research with the aim of discovering new therapeutic targets. The nuclear hormone receptor, PPAR is now a recognised modulator of inflammation in various chronic inflammatory conditions, but its role in the persistent airways inflammation in COPD has not been examined. Control of the inflammatory response by PPAR has been shown by antagonising inflammatory signalling pathways, such as NF-B and AP-1.

PPAR protein levels in lung tissue from patients with COPD were assessed by Western blot. In vitro assays using the human type II alveolar epithelial cell line were performed to assess the effect of PPAR agonist treatment on inflammatory cytokine generation.

An increase in PPAR protein levels was seen for healthy smokers compared with non-smokers (Ratio to ß-actin loading control, non-smokers 0.61±0.1, n = 10; healthy smokers 0.97±0.3, n = 11, p>0.05). No increase was seen for current smoker or ex-smoker COPD patients (0.36±0.08, n = 12; 0.49±0.1, n = 8 respectively). In vitro experiments with a human type II alveolar epithelial cell line demonstrated a diminished inflammatory response to TNF, as measured by the generation of the pro-inflammatory cytokine IL-8, following pre-treatment with the PPAR agonist, WY-14643 (IL-8 generation, control 823±22 pg·ml^–1, TNF 7491±530 pg·ml^–1 p<0.001, WY-14643 2559±46 pg·ml^–1 p<0.05, n = 3).

We propose PPAR agonists as a potential therapy for reducing the NF-B-regulated inflammation in COPD airways.

Supported by GlaxoSmithKline