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.

Omega-3 PUFA docosahexaenoic acid decreases LPS-stimulated MUC5AC production by altering EGFR-related signaling in NCI-H292 cells

“…In colonic cells, DHA reduces wound-induced EGFR transactivation. Moreover, under wounding conditions, the suppression of EGFR activation is associated with a reduction in downstream activation of cytoskeletal remodeling proteins such as Rac1, as well as a reduced cell migration [22]. These observations are consistent with our findings in human airway cells and suggest that inhibition of both EGFR transactivation and downstream signaling by DHA could be independent of the cell type.…”

Mechanisms by Which Pleiotropic Amphiphilic n−3 PUFA Reduce Colon Cancer Risk

“…There is a growing body of experimental, epidemiological, and preclinical evidence indicating that n –3 PUFA, mainly DHA and EPA, are protective against colon tumorigenesis [9, 153–157]. Establishing a causal role of n –3 PUFA in colon cancer prevention would have a major translational impact because these dietary nutrients are safe, well tolerated [158], and relatively inexpensive and provide additional health benefits, such as reduction in mortality [159].…”

“…DHA also modulates the levels and localization of a critical signaling lipid, phosphoinositide 4,5-bis-phosphate (PIP 2 ) [160••]. This in turn reduces filamentous actin remodeling as well as activation of cytoskeletal regulators, Rac1 and Cdc42, which in turn reduces cell migration [157, 160••]. Cholesterol and the cytoskeleton are major contributors to maintaining membrane order.…”

Is the omega-3 index a valid marker of intestinal membrane phospholipid EPA+DHA content?

“…In the present study, we investigated the effect of increasing EPA+DHA content of soybean oil-based AIN-93G; however, others have investigated the lipid composition of various tissues from mice fed diets with non-standard lipid mixtures [7, 24, 25]. At least two studies that have reported the fatty acid composition of colonic mucosa where the lipid in the diet was primarily low in alpha-linolenic (ALA; 18:3n-3), such as canola or corn oil, have observed low levels of DHA (1.3% [24], 1.6% [7].…”