TY - JOUR

T1 - Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

AU - Prihandoko, Rudi

AU - Kaur, Davinder

AU - Wiegman, Coen H.

AU - Alvarez-Curto, Elisa

AU - Donovan, Chantal

AU - Chachi, Latifa

AU - Ulven, Trond

AU - Tyas, Martha R.

AU - Euston, Eloise

AU - Dong, Zhaoyang

AU - Alharbi, Abdulrahman Ghali M.

AU - Kim, Richard Y.

AU - Lowe, Jack G.

AU - Hansbro, Philip M.

AU - Chung, Kian Fan

AU - Brightling, Christopher E.

AU - Milligan, Graeme

AU - Tobin, Andrew B.

PY - 2020

Y1 - 2020

N2 - 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 G(q/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 E-2 (PGE(2)) 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.

AB - 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 G(q/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 E-2 (PGE(2)) 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.

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - SMOOTH-MUSCLE-CELLS

KW - INSULIN-RESISTANCE

KW - GPR120 FFAR4

KW - EP4 RECEPTOR

KW - AIRWAY

KW - PGE(2)

KW - POTENT

KW - PHOSPHORYLATION

KW - AGONIST

U2 - 10.1126/scitranslmed.aaw9009

DO - 10.1126/scitranslmed.aaw9009

M3 - Journal article

C2 - 32817367

VL - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 557

M1 - 9009

ER -