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Ionic components of electric current at rat corneal wounds.

Vieira AC, Reid B, Cao L, Mannis MJ, Schwab IR, Zhao M - PLoS ONE (2011)

Bottom Line: After wounding, Ca(2+) efflux increased steadily whereas K(+) showed an initial large efflux which rapidly decreased.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of California Davis, Davis, California, United States of America.

ABSTRACT

Background: Endogenous 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 findings: Using 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, Ca(2+) 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/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. Ca(2+) 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.

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Which ions contribute to the wound electric current?The corneal epithelium transports ions to generate and maintain a transepithelial potential difference (TEPD) of ∼25–45 mV. Injury breaks the epithelial barrier and collapses the potential at the wound (left). The positive potential in the surrounding intact epithlium drives ion current flow out of the wound (blue arrows) and forms laterally-orientated wound electric fields (red arrow) with the wound the cathode.
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pone-0017411-g001: Which ions contribute to the wound electric current?The corneal epithelium transports ions to generate and maintain a transepithelial potential difference (TEPD) of ∼25–45 mV. Injury breaks the epithelial barrier and collapses the potential at the wound (left). The positive potential in the surrounding intact epithlium drives ion current flow out of the wound (blue arrows) and forms laterally-orientated wound electric fields (red arrow) with the wound the cathode.

Mentions: The mechanisms of how the electric currents are generated and maintained however remain very poorly understood and largely unstudied. It is generally assumed that the wound electric currents are caused by a short-circuit of the trans-epithelial potential difference (TEPD) at the wound site. In another words, a passive leakage of ions and other charged molecules. The TEPD is a common feature of most epithelia, including skin and corneal epithelia. In the cornea, ions are constantly being transported across the corneal epithelium, which generates and maintains the TEPD with the outer side negative [25]. Sodium ions are actively transported from the tears to the aqueous humor while chloride ions are pumped in the opposite direction, towards the tear side (Fig. 1) [26]–[28]. Tight junctions between epithelial cells form a high resistance barrier to minimize ion leakage and maintain the TEPD. Damage to the corneal epithelium disrupts the tight junctional barrier and the TEPD collapses at the wound. The electrically positive TEPD under the surrounding intact epithelium thus drives a laterally-oriented electric field running from the intact cornea across the wound edge into the wound center, with the wound the negatively-charged cathode (Fig. 1). Human corneal epithelial cells migrate to the cathode in vitro [15]–[18] and increasing cornea wound current pharmacologically enhances wound healing [6].


Ionic components of electric current at rat corneal wounds.

Vieira AC, Reid B, Cao L, Mannis MJ, Schwab IR, Zhao M - PLoS ONE (2011)

Which ions contribute to the wound electric current?The corneal epithelium transports ions to generate and maintain a transepithelial potential difference (TEPD) of ∼25–45 mV. Injury breaks the epithelial barrier and collapses the potential at the wound (left). The positive potential in the surrounding intact epithlium drives ion current flow out of the wound (blue arrows) and forms laterally-orientated wound electric fields (red arrow) with the wound the cathode.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045448&req=5

pone-0017411-g001: Which ions contribute to the wound electric current?The corneal epithelium transports ions to generate and maintain a transepithelial potential difference (TEPD) of ∼25–45 mV. Injury breaks the epithelial barrier and collapses the potential at the wound (left). The positive potential in the surrounding intact epithlium drives ion current flow out of the wound (blue arrows) and forms laterally-orientated wound electric fields (red arrow) with the wound the cathode.
Mentions: The mechanisms of how the electric currents are generated and maintained however remain very poorly understood and largely unstudied. It is generally assumed that the wound electric currents are caused by a short-circuit of the trans-epithelial potential difference (TEPD) at the wound site. In another words, a passive leakage of ions and other charged molecules. The TEPD is a common feature of most epithelia, including skin and corneal epithelia. In the cornea, ions are constantly being transported across the corneal epithelium, which generates and maintains the TEPD with the outer side negative [25]. Sodium ions are actively transported from the tears to the aqueous humor while chloride ions are pumped in the opposite direction, towards the tear side (Fig. 1) [26]–[28]. Tight junctions between epithelial cells form a high resistance barrier to minimize ion leakage and maintain the TEPD. Damage to the corneal epithelium disrupts the tight junctional barrier and the TEPD collapses at the wound. The electrically positive TEPD under the surrounding intact epithelium thus drives a laterally-oriented electric field running from the intact cornea across the wound edge into the wound center, with the wound the negatively-charged cathode (Fig. 1). Human corneal epithelial cells migrate to the cathode in vitro [15]–[18] and increasing cornea wound current pharmacologically enhances wound healing [6].

Bottom Line: After wounding, Ca(2+) efflux increased steadily whereas K(+) showed an initial large efflux which rapidly decreased.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of California Davis, Davis, California, United States of America.

ABSTRACT

Background: Endogenous 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 findings: Using 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, Ca(2+) 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/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. Ca(2+) 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.

Show MeSH
Related in: MedlinePlus