Diminished Peroxisome Proliferator-activated Receptor (ppar) Regulation as a Potential Mechanism for the Persistent Inflammation in Chronic Obstructive Pulmonary Disease

WINNING ABSTRACT: 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 PPARa has been shown by antagonising inflammatory signalling pathways, such as NF-kB and AP-1. PPARa 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 PPARa agonist treatment on inflammatory cytokine generation. An increase in PPARa protein levels was seen for healthy smokers compared with non-smokers (Ratio to b-actin loading control, non-smokers 0.61¡0.1, n510; healthy smokers 0.97¡0.3, n511, p.0.05). No increase was seen for current smoker or ex-smoker COPD patients (0.36¡0.08, n512; 0.49¡0.1, n58 respectively). In vitro experiments with a human type II alveolar epithelial cell line demonstrated a diminished inflammatory response to TNFa, as measured by the generation of the proinflammatory cytokine IL-8, following pre-treatment with the PPARa agonist, WY-14643 (IL-8 generation, control 823¡22 pg?ml, TNFa 7491¡530 pg?ml p,0.001, WY-14643 2559¡46 pg?ml p,0.05, n53). We propose PPAR agonists as a potential therapy for reducing the NF-kB-regulated inflammation in COPD airways. Supported by GlaxoSmithKline