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 omega-3 polyunsaturated fatty acids. Its expression has been reported in lung epithelial club cells. We investigated whether supplementation of the omega-3 fatty acids benefits lung health. Omacor (7.75 mg/kg), clinically prescribed preparation of omega-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, omega-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 omega-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 omega-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 omega-3 fatty acids stimulate proliferation but inhibit differentiation of club cells.