title: Inhibitory effects of omega-3 fatty acids on injury-induced epidermal growth factor receptor transactivation contribute to delayed wound healing.
abstract: Epidermal growth factor receptor (EGFR)-mediated signaling is required for optimal intestinal wound healing. Since n-3 polyunsaturated fatty acids (PUFA), specifically docosahexaenoic acid (DHA), alter EGFR signaling and suppress downstream activation of key signaling pathways, we hypothesized that DHA would be detrimental to the process of intestinal wound healing. Using a mouse immortalized colonocyte model, DHA uniquely reduced EGFR ligand-induced receptor activation, whereas DHA and its metabolic precursor eicosapentaenoic acid (EPA) reduced wound-induced EGFR transactivation compared with control (no fatty acid or linoleic acid). Under wounding conditions, the suppression of EGFR activation was associated with a reduction in downstream activation of cytoskeletal remodeling proteins (PLCγ1, Rac1, and Cdc42). Subsequently, DHA and EPA reduced cell migration in response to wounding. Mice were fed a corn oil-, DHA-, or EPA-enriched diet prior to intestinal wounding (2.5% dextran sodium sulfate for 5 days followed by termination after 0, 3, or 6 days of recovery). Mortality was increased in EPA-fed mice and colonic histological injury scores were increased in EPA- and DHA-fed mice compared with corn oil-fed (control) mice. Although kinetics of colonic EGFR activation and downstream signaling (PLCγ1, Rac1, and Cdc42) were delayed by both n-3 PUFA, colonic repair was increased in EPA- relative to DHA-fed mice. These results indicate that, during the early response to intestinal wounding, DHA and EPA uniquely delay the activation of key wound-healing processes in the colon. This effect is mediated, at least in part, via suppression of EGFR-mediated signaling and downstream cytoskeletal remodeling.
authors: Program in Integrative Nutrition and Complex Diseases, Texas A & M University, College Station, TX 77843, USA.
authors: Harmony F
authors: HF
authors: Turk
authors: Jennifer M
authors: JM
authors: Monk
authors: Yang-Yi
authors: YY
authors: Fan
authors: Evelyn S
authors: ES
authors: Callaway
authors: Brad
authors: B
authors: Weeks
authors: Robert S
authors: RS
authors: Chapkin
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003314:Corn Oil / Q000008:administration & dosage; D016264:Dextran Sulfate; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000502:physiology; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage* / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010101:Oxygen Consumption; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014945:Wound Healing; D017962:alpha-Linolenic Acid / Q000494:pharmacology / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: C581598:Cdc42 protein, mouse; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D017962:alpha-Linolenic Acid; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D003314:Corn Oil; D016264:Dextran Sulfate; D015118:Eicosapentaenoic Acid; D066246:ErbB Receptors; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
keywords: colonic wounding; epidermal growth factor receptor; epithelial restitution; n-3 polyunsaturated fatty acids