Proinflammatory Roles Of Fibroblasts Under Dehydration In Open Wounds
ping xie, David Dolivo, Seok Hong, Robert D. Galiano, Thomas A. Mustoe.
northwestern university, Chicago, IL, USA.
Backgrounds: Wound healing is a complex multicellular process involving a series of overlapping phases, including coagulation, inflammation, granulation tissue formation, and remodeling. The presence of a prolonged inflammatory phase has been demonstrated during wound repair under dry conditions, concomitant with a delay in the wound healing process. Disruption of dermal integrity leads to evaporative water loss, which subsequently results in an increase in extracellular sodium concentration. We have previously demonstrated that water loss or high salt treatment promotes an inflammatory responses in keratinocytes, which is partially mediated through the sodium channel NaX. In addition to their role in the synthesis of extracellular matrix, fibroblasts, as the predominant resident cell type in wounds, are able to produce and release various pro-inflammatory cytokines when they encounter external stimuli. In this study we investigated whether fibroblasts are involved in the inflammatory response under dry condition during wound healing. Methods and Results: Here we show that exposure to air (dehydration) induced upregulation of pro-inflammatory cytokines IL-8 and Cox-2 in non-epithelialized wounds on rabbit ears, concomitant with increased infiltration of neutrophils. Ex vivo, the granulation tissue containing numerous fibroblasts was excised from wounds and exposed to a 10% increase in sodium within the culture media (high salt treatment), under which the expression of IL8 and PTGS2 (the gene encoding COX-2) was upregulated. In vitro, high expression of NaX was detected in fibroblasts. Exposure of fibroblasts to high salt culture media led to an increase of expression of IL8 and PTGS2, which was able to be blocked by knockdown of NaX using shRNA. Conclusions: These data suggest that the local dehydration stimulus to open wounds increased inflammation in fibroblasts via NaX activation and signaling.
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