Fibroblast Mediated Nax Signaling Drives Inflammation In Open Wounds
Huining Bian, Ping Xie, Elena Bogdanovic, Emily Elizabeth Friedrich, Seok Jong Hong, Robert Galiano, Thomas Mustoe.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
BACKGROUND The skin provides a barrier between the outside environment and the internal milieu of the body. Disruption of the stratum corneum which occurs in wounding leads to evaporative water loss and we hypothesize an increase in [Na+]. We have previously shown that when keratinocytes are exposed to a 10% increase in extracellular [Na+] - which could potentially occur in open wounds, the sodium channel NaX becomes permeable leading to the influx of Na+. The resultant increase in intracellular [Na+] in-turn activates signaling pathways leading to inflammation and scar formation. METHODS Fibroblasts are crucial to the wound healing process by stimulating the production of collagen for tissue repair. Fibroblasts may also serve as vital immunoregulatory cells.Me In this study we investigated whether exposure of fibroblasts to increases in extracellular [Na+] could modulate fibroblast function during wound healing. Here we show that under dehydrating conditions, in non-epithelized wounds where fibroblasts are the predominant cell type, the inflammatory mediators Cox-2 and Il-8 are markedly upregulated. RESULTS In vitro, NaX is highly expressed in fibroblasts and exposure of fibroblasts to a 10% increase in culture media [Na+] led to a rapid influx of Na+ and upregulated the expression of COX-2 and IL-8. Knock-down of NaX expression using shRNA blocked the induction of COX-2 and IL-8 in response to high NaCl. In the presence of increased NaCl collagen contraction and cell migration were not affected suggesting that high Na+ preferentially modulates the inflammatory signaling pathways within fibroblasts. CONCLUSIONS These data suggest that increases in local [Na+] such as those that would occur in an open wound stimulate inflammation in fibroblasts via NaX activation and signaling.
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