Hydration Status Regulates Sodium Flux and Inflammatory Pathways through Epithelial Sodium Channel (ENaC) in the Skin (original) (raw)

2014, Journal of Investigative Dermatology

Although it is known that the inflammatory response which results from disruption of epithelial barrier function after injury results in excessive scarring, the upstream signals remain unknown. It has also been observed that epithelial disruption results in reduced hydration status and that the use of occlusive dressings which prevent water loss from wounds decreases scar formation. We hypothesized that hydration status changes sodium homeostasis and induces sodium flux in keratinocytes, which result in activation of pathways responsible for keratinocyte-fibroblast signaling, and ultimately lead to activation of fibroblasts. Here, we demonstrate that perturbations in epithelial barrier function lead to increased sodium flux in keratinocytes. We identified that sodium flux in keratinocytes is mediated by epithelial sodium channels (ENaC) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the COX-2/ prostaglandin E 2 (PGE 2 ) pathway. Similar changes in signal transduction and sodium flux occur by increased sodium concentration, which simulates reduced hydration, in the media in epithelial cultures, or human ex vivo skin cultures (HESC). Blockade of ENaC, prostaglandin synthesis, or PGE 2 receptors all reduce markers of fibroblast activation and collagen synthesis. In addition, employing a validated in vivo excessive scar model in the rabbit ear, we demonstrate that utilization of either an ENaC blocker or a COX-2 inhibitor results in a marked reduction in scarring. Other experiments demonstrate that the activation of COX-2 in response to increase sodium flux is mediated through the PIK3/Akt pathway. Our results indicate that ENaC responds to small changes in sodium concentration with inflammatory mediators, and suggests that ENaC pathway is a potential target for a strategy to prevent fibrosis. De Jongh CM, Verberk MM, Withagen CE, et al. 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