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

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Science Translational Medicine  19 Aug 2020:
Vol. 12, Issue 557, eaaw9009
DOI: 10.1126/scitranslmed.aaw9009

Breathing easy

Asthma and chronic obstructive pulmonary disease result in airway swelling that hinders breathing. Prihandoko et al. found that intranasal delivery of a free fatty acid receptor 4 (FFA4) agonist reduced airway resistance in mouse models of acute and chronic ozone pollution–mediated inflammation as well as house dust mite and cigarette smoke–induced inflammation. This airway relaxation was mediated in part by the release of prostaglandin PGE2. FFA4 agonism also mediated smooth muscle relaxation of ex vivo human airway samples, suggesting FFA4 as a potential respiratory disease target in humans.


Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. 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 E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke–induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

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