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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1126/scitranslmed.aaw9009
Journal or Publication Title: Science Translational Medicine
Volume: 12
Number: 557
Page Range: eaaw9009
Date: 2020
Divisions: UTS Centre for Inflammation
Depositing User: General Admin
Identification Number: 10.1126/scitranslmed.aaw9009
ISSN: 1946-6234
Date Deposited: 04 Jan 2021 02:32
Abstract:

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.

Creators:
Creators
Email
Prihandoko, Rudi
UNSPECIFIED
Kaur, Davinder
UNSPECIFIED
Wiegman, Coen H.
UNSPECIFIED
Alvarez-Curto, Elisa
UNSPECIFIED
Donovan, Chantal
UNSPECIFIED
Chachi, Latifa
UNSPECIFIED
Ulven, Trond
UNSPECIFIED
Tyas, Martha R.
UNSPECIFIED
Euston, Eloise
UNSPECIFIED
Dong, Zhaoyang
UNSPECIFIED
Alharbi, Abdulrahman Ghali M.
UNSPECIFIED
Kim, Richard Y.
UNSPECIFIED
Lowe, Jack G.
UNSPECIFIED
Hansbro, Philip M.
UNSPECIFIED
Chung, Kian Fan
UNSPECIFIED
Brightling, Christopher E.
UNSPECIFIED
Milligan, Graeme
UNSPECIFIED
Tobin, Andrew B.
UNSPECIFIED
Last Modified: 04 Jan 2021 02:32
URI: https://eprints.centenary.org.au/id/eprint/776

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