TY - JOUR
T1 - Hydration status regulates sodium flux and inflammatory pathways through epithelial sodium channel (ENaC) in the skin
AU - Xu, Wei
AU - Hong, Seok Jong
AU - Zeitchek, Michael
AU - Cooper, Garry
AU - Jia, Shengxian
AU - Xie, Ping
AU - Qureshi, Hannan A.
AU - Zhong, Aimei
AU - Porterfield, Marshall D.
AU - Galiano, Robert D.
AU - Surmeier, D. James
AU - Mustoe, Thomas A.
N1 - Funding Information:
We thank the Keratinocyte Core of Northwestern University Skin Disease Research Center for the infant foreskin keratinocyte culture. We also thank Vinay Rawlani, Sue Jordan, Shin Yoo, and Ian Chow for the critical review of the manuscript. This work was supported by internal funding from Division of Plastic and Reconstructive Surgery, Northwestern University, and Feinberg School of Medicine.
Publisher Copyright:
© 2015 The Society for Investigative Dermatology.
PY - 2015/3/12
Y1 - 2015/3/12
N2 - Although it is known that the inflammatory response that 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 that 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 (ENaCs) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the cyclooxygenase 2 (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. 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 increased 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 suggest that the ENaC pathway is a potential target for a strategy to prevent fibrosis.
AB - Although it is known that the inflammatory response that 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 that 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 (ENaCs) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the cyclooxygenase 2 (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. 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 increased 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 suggest that the ENaC pathway is a potential target for a strategy to prevent fibrosis.
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U2 - 10.1038/jid.2014.477
DO - 10.1038/jid.2014.477
M3 - Article
C2 - 25371970
AN - SCOPUS:84922636594
SN - 0022-202X
VL - 135
SP - 796
EP - 806
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 3
ER -