Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with a significant number of patients being inadequately controlled by current frontline treatments means that there is a need to define novel therapeutic targets for these conditions 1 . Here we investigate a member of the G protein-coupled receptor (GPCR) family, FFA4, which responds to free circulating fatty acids, including dietary omega-3 fatty acids found in fish oils 2–4 . Although usually associated with metabolic responses linked with food intake, we show that FFA4 is expressed in the lung where it is coupled to G q/11 -signalling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated, at least in part, by the release of the prostaglandin PGE 2 that subsequently acts on EP 2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. Importantly, in acute and chronic ozone models of pollution-mediated inflammation, and in house-dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, whilst this response was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was very similar to that observed in mice and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation. Hence, our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy that might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.