Prostanoid receptors as targets for asthma and COPD therapy

Asthma is an inflammatory disease of the lung that affects a large percentage of the population in the Western world and represents a huge health care burden and is characterised by chest tightness and breathing difficulties. There are 5.2 million asthma sufferers in the UK, 1.1 million children (1 in 10) and 4.1 million adults (1 in 12). On average, 1400 people die from asthma each year, and asthma now costs the NHS an average of #889 million per year. The Global Burden of Disease studies ranked COPD as the 6th commonest cause of death worldwide in 1990 and this has now risen to 4th. In the UK COPD now causes about 30,000 deaths a year and mortality is almost double the European average, with COPD killing more women than breast cancer last year.Inflammation is believed to be central to the development and symptoms of asthma and COPD. A naturally occurring chemical in the body can open the airways and reduce the inflammation through interactions with one or more of a family of proteins. Unfortunately, this chemical also causes cough. The aim of this study is to try to determine which of the proteins are involved in the beneficial responses and which in the detrimental cough response of the chemical. The hope is that this work may lead to the discovery of a novel drug which could selectively target the beneficial processes leading to the production of a therapy that could help these patients who suffer from these debilitating diseases.

In the clinic, patients with asthma and COPD are treated with either beta-agonists to induce bronchodilatation, or steroids to control the underlying airway inflammation observed in this disease. The prostanoid, PGE2 has been reported to induce bronchodilatation in animals and humans, and confers certain advantages over existing bronchodilators due to its anti-inflammatory potential. However, PGE2 also causes airway irritancy and cough. Prostanoids act at G-protein coupled receptors, of which five main classes have been identified. The EP-receptor also exists in four subtypes. PGE2 relaxes smooth muscle (possibly via activation of the EP2 receptor) and is anti-inflammatory (receptor not known). Furthermore, the receptor that induces cough has not been characterised. It is, therefore, possible that the EP-receptor subtype mediating irritancy and cough differs from that mediating bronchodilatation and anti-inflammatory effects. The current proposal aims to classify the receptor(s) through which prostanoids act to stimulate airway vagal sensory nerves, nerves that are instrumental in orchestrating the cough reflex. In addition, we also aim to investigate the receptors involved in evoking the anti-inflammatory effects attributed to prostanoids under both normal and disease conditions. This work may highlight a bronchodilator and anti-inflammatory agonist devoid of side-effects that may be formulated as an anti-asthma/COPD therapy.