title: Mitigation of indomethacin-induced gastrointestinal damages in fat-1 transgenic mice via gate-keeper action of ω-3-polyunsaturated fatty acids.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastrointestinal (GI) epithelial cell membranes by inducing several signals through lipid raft organization after membrane incorporation, whereas ω-3 polyunsaturated fatty acids (PUFAs) relieve inflammation, reduce oxidative stress, and provide cytoprotection, consequent to lipid raft disorganization. Therefore, we hypothesized that ω-3 PUFAs can protect the GI from NSAID-induced damages by initiating the gatekeeper action of cell membranes, subsequent to anti-inflammatory and anti-oxidative actions. Administration of indomethacin (IND) leads to the formation of lipid rafts and activation of caveolin-1; however, no such observations were made upon co-administration of eicosapentaenoic acid (EPA) and IND. In addition, the EPA-induced lipid raft disorganization, caveolin-1 inactivation, and cellular cytotoxicity were inhibited when target cells were knocked-out using G-protein coupled receptor 120 (GPR 120). EPA significantly attenuated IND-induced oxidative damage and apoptosis. IND administration induced significant ulceration, bleeding, and oedema in the stomach or small intestine of wild-type (WT) mice; however, such severe damages to the GI significantly decreased in fat-1 transgenic (TG) mice (P < 0.001), which exhibited decreased cyclooxygenase-2 expression and apoptosis, decreased interleukin-1β and FAS concentrations, and increased heme oxygenase-1 concentration. Our study indicates that the gatekeeper function of ω-3 PUFAs improves GI safety when administered with NSAID.
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Han
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
authors.affiliation: Lee Gil Ya Diabetes and Cancer Institute, Gachon University, Incheon, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Cha
authors.affiliation: Lee Gil Ya Diabetes and Cancer Institute, Gachon University, Incheon, Korea.
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea.
authors.forename: Migeyong
authors.initials: M
authors.lastname: Jeong
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Go
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea.|Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
authors.forename: Ki Baik
authors.initials: KB
authors.lastname: Hahm