Characterising the prostanoid receptor(s) through which PGE2 modulates airway smooth muscle tone.

James Buckley, Sarah Maher, Deborah Clarke, Mark Birrell, Maria Belvisi. Imperial College, London, United Kingdom.

Prostaglandin E2 (PGE2) has been previously demonstrated to have significant bronchodilator and anti-inflammatory properties. However attempts to utilize these beneficial effects as a potential therapy for the treatment of respiratory diseases such as asthma and COPD have been hampered due to other, unwanted effects of PGE2 (e.g. cough). In order to select out the beneficial effects of PGE2, it is necessary to determine which prostanoid receptor (PR) is central to each of the various activities of PGE2. The aim of this study was to determine which PR PGE2 acts on to modulate airway smooth muscle (ASM) tone.

Isolated tracheal tissue (n=2-6) from male guinea-pigs (gp - Dunkin Hartley, 300-350g) or C57/BL6 mice (16-20gm, wild type or PR gene deleted mice) were set up in tissue baths containing oxygenated and indomethacin-containing (10-5M) Krebs maintained at 37°C. The tissues were exposed to vehicle (ethanol) or PGE2 (10-10-10-5M) under carbachol-induced tone (1µM) and in some cases the tissues were pre-incubated with vehicle (DMSO, 0.1% v/v) or PR antagonist for 30 minutes prior to PGE2 administration.

Under induced tone PGE2 caused relaxation of gp tissue (1.6 ± 0.2 gm, 56.4 ± 3.0 % of maximum relaxation to 100µM papaverine). This response was not modulated by the selective EP1, EP3 and EP4 antagonists used. However, the EP1/EP2/DP1 antagonist AH6809 caused a rightward shift in the PGE2 response curve suggesting that the dominant PR involved in relaxing ASM is the EP2 receptor. To help confirm this finding we exposed tracheal tissue from transgenic mice lacking individual EP PRs to PGE2 (Figure 1).

Figure 1: Response to PGE2 of tracheal tissue taken from wild type and EP receptor deficient mice

In summary, we believe this to be the first study to use a combination of the latest pharmacological tools and ASM tissue from various EP receptor KO mice to show that PGE2 acts partially on the EP2 receptor to relax isolated tracheal tissue. We are currently trying to determine the receptor responsible for the remaining relaxation response to PGE2.