Nonsteroidal anti-inflammatory drugs inhibit re-epithelialization of wounded gastric monolayers by interfering with actin, Src, FAK, and tensin signaling

Re-epithelialization is essential for gastrointestinal ulcer and cutaneous wound healing. It requires epithelial cell migration and proliferation, pro cesses that are stimulated by epidermal growth factor (EGF), and dependent on the cell cytoskeleton. Activation of Src and focal adhesion kinase (FAK) has been implicated in EGF-stimulated cell migration. Nonsteroidal anti-in flammatory drugs (NSAIDs) (both nonselective and Cox2-selective) interfere with ulcer healing and re-epithelialization in vitro and in vivo, but the c ellular targets and mechanisms remain unexplored forming the basis of this study. Using a wounded gastric epithelial cell monolayer model, we demonstr ated that NSAIDs reduce both basal and epidermal growth factor (EGF)-induce d re-epithelialization, and that this action involves disruption of actin s tress fiber formation, reduced c-Src activity, decreased phosphorylation of focal adhesion kinase (FAK), tensin and their cellular re-distribution. Th ere was a strong correlation between NSAIDs-mediated inhibitory effect on r e-epithelialization and loss of stress fibers and reduced tensin signal. Fu rthermore, NSAIDs significantly reduced EGF-stimulated c-Src association wi th FAK. These findings suggest that NSAIDs can directly affect the cell cyt oskeleton and signaling pathways essential for re-epithelialization. (C) 20 01 Elsevier Science Inc. All rights reserved.