Genomic effects of GW0742, a peroxisome proliferator activated receptor (PPAR) β/δ agonist on rat bronchi

Louise Harrington, Kira Achaibar, Anna Reed, Laura Moreno, Jane Mitchell. NHLI, Imperial College, SW3 6LY, United Kingdom.

Peroxisome Proliferator activated receptors (PPARs) are therapeutic targets in the treatment of inflammatory lung disease. We have recently shown that the PPARβ/δ agonist GW0742 relaxes pulmonary, aorta and mesenteric arteries in mice, and has therapeutic benefits in pulmonary hypertension in rats (Harrington et al, 2010). Despite evidence of ubiquitous PPARβ/δ expression relatively little is known about its effects in the airways

Male Sprague Dawley rats (200-250g) were killed by cervical dislocation, and the bronchi mounted into isometric wire myographs. Bronchi were contracted with EC80 concentrations of acetylcholine (Ach) and responses to increasing concentrations of GW0742 (10-6 to 10-4M) measured. Some bronchi were incubated for 16 hours with GW0742 (3 × 10-5M) and/or the protein synthesis inhibitor cyclohexamide (CHX; 1.4 × 10-5M) at 37.5°C, before contractions to Ach measured. Rat bronchi did not relax in response to GW0742 given acutely at concentrations up to 10-4M, where 33.4 ± 5.1% SEM relaxation was seen compared to -10.4 ± 2.8% SEM in time controls (n = 4). Overnight incubation (chronic exposure) of airway tissue with 3 × 10-5M GW0742 reduced broncho-contraction in response to Ach (Figure 1) an effect that was prevented by co-incubation with CHX (Figure 1).

Figure 1. Effect of 16hr incubation with GW0742 +/- Cyclohexamide on Acetylcholine induced broncho-contraction. Data shown is mean ± SEM, n = 3; * p<0.05 by two way ANOVA compared to control or GW0742 plus CHX.

These findings suggest that activation of PPARβ/δ and subsequent gene induction/new protein synthesis protects the airways from bronchospasm and may have therapeutic indications in inflammatory lung diseases.

Harrington et al, 2010 PloS ONE 5(3) e9526.