Abstract
BackgroundEndogenous electric fields and currents occur naturally at wounds and are a strong signal guiding cell migration into the wound to promote healing. Many cells involved in wound healing respond to small physiological electric fields in vitro. It has long been assumed that wound electric fields are produced by passive ion leakage from damaged tissue. Could these fields be actively maintained and regulated as an active wound response? What are the molecular, ionic and cellular mechanisms underlying the wound electric currents?Methodology/Principal FindingsUsing rat cornea wounds as a model, we measured the dynamic timecourses of individual ion fluxes with ion-selective probes. We also examined chloride channel expression before and after wounding. After wounding, Ca2+ efflux increased steadily whereas K+ showed an initial large efflux which rapidly decreased. Surprisingly, Na+ flux at wounds was inward. A most significant observation was a persistent large influx of Cl−, which had a time course similar to the net wound electric currents we have measured previously. Fixation of the tissues abolished ion fluxes. Pharmacological agents which stimulate ion transport significantly increased flux of Cl−, Na+ and K+. Injury to the cornea caused significant changes in distribution and expression of Cl− channel CLC2.Conclusions/SignificanceThese data suggest that the outward electric currents occurring naturally at corneal wounds are carried mainly by a large influx of chloride ions, and in part by effluxes of calcium and potassium ions. Ca2+ and Cl− fluxes appear to be mainly actively regulated, while K+ flux appears to be largely due to leakage. The dynamic changes of electric currents and specific ion fluxes after wounding suggest that electrical signaling is an active response to injury and offers potential novel approaches to modulate wound healing, for example eye-drops targeting ion transport to aid in the challenging management of non-healing corneal ulcers.
Highlights
At human skin wounds, naturally occurring electric fields and currents were detected many years ago [1,2,3,4]
The cornea was wounded as above and measurements made at the left wound edge (Fig. 2C). This position was chosen since we previously showed that the current at the wound edge was significantly greater than at the wound center, indicating substantial ion pumping and/or leakage at the cut edge of the corneal epithelium [6]
We previously showed that drugs which affect ion flux alter cornea wound electric current and rate of wound healing [6,34]
Summary
Naturally occurring electric fields and currents were detected many years ago [1,2,3,4]. Conclusions/Significance: These data suggest that the outward electric currents occurring naturally at corneal wounds are carried mainly by a large influx of chloride ions, and in part by effluxes of calcium and potassium ions.
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