ω-3 Polyunsaturated fatty acids accelerate airway repair by activating FFA4 in club cells.
A G protein-coupled receptor (GPCR) named free fatty acid receptor 4 (FFA4, also known as GPR120) was found to act as a GPCR for ω-3 polyunsaturated fatty acids. Its expression has been reported in lung epithelial club cells. We investigated whether supplementation of the ω-3 fatty acids benefits lung health. Omacor (7.75 mg/kg), clinically prescribed preparation of ω-3 fatty acids, and FFA4-knockout mice were utilized in a naphthalene-induced mouse model of acute airway injury (1 injection of 30 mg/kg ip). Naphthalene injection induced complete destruction of bronchiolar epithelial cells within a day. Appearance of bronchiolar epithelial cells was observed after 21 days in control mice. It was found, however, that supplementation of Omacor accelerated the recovery. The appearance of bronchiolar epithelial cells was observed between 7 and 14 days after naphthalene injury in Omacor-treated mice. In isolated club cells, ω-3 fatty acids were found to stimulate cell proliferation and migration but to inhibit cell differentiation. With the use of pharmacological tools and FFA4-knockout mice, FFA4 was found to be responsible for ω-3 fatty acids-induced proliferation in vitro in club cells. Furthermore, accelerated recovery from naphthalene-induced airway injury in Omacor-treated mice was not observed in FFA4-knockout mice in vivo. Present findings indicate that ω-3 fatty acids-induced proliferation of bronchiole epithelial cells through FFA4 is responsible for Omacor-induced accelerated recovery from airway injury. Therefore, intermittent administration of Omacor needs to be tested for acute airway injury because ω-3 fatty acids stimulate proliferation but inhibit differentiation of club cells.
Molecular Inflammation Research Center for Aging Intervention and College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Kyoung-Pil
KP
Lee
Molecular Inflammation Research Center for Aging Intervention and College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Soo-Jin
SJ
Park
Molecular Inflammation Research Center for Aging Intervention and College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Saeromi
S
Kang
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; and.
Jung-Min
JM
Koh
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Showa-machi, Maebashi, Japan.
Koichi
K
Sato
Molecular Inflammation Research Center for Aging Intervention and College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Hae-Young
HY
Chung
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Showa-machi, Maebashi, Japan.
Fumikazu
F
Okajima
Molecular Inflammation Research Center for Aging Intervention and College of Pharmacy, Pusan National University, Busan, Republic of Korea; imds@pusan.ac.kr.
Dong-Soon
DS
Im
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004338:Drug Combinations; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D008168:Lung / Q000473:pathology*; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009281:Naphthalenes; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*
D004338:Drug Combinations; C498007:FFAR4 protein, mouse; D015525:Fatty Acids, Omega-3; D009281:Naphthalenes; D043562:Receptors, G-Protein-Coupled; C031721:naphthalene; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; C405603:Omacor
FFA4; GPR120; airway injury; club cell; docosahexaenoic acid; ω-3 fatty acid