Therapeutic benefits of gap junction inhibitors in chronic wound healing events

Catherine Wright, Malcolm B. Hodgins, Patricia Martin

Research output: Contribution to conferencePaper

Abstract

Non-healing cutaneous wounds, a major cause of morbidity and mortality, are difficult to treat. Recent studies suggest significant increases in skin wound-healing rates occur by altering gap junction intercellular communication (GJIC). Agents that directly target specific gap junction subunits, or connexins (Cx), such as connexin mimetic peptides, are emerging as attractive therapeutic targets.
We analysed the effect of these peptides on cell-cell communication and cell migration responses during wound healing. We first established robust 2D and 3D human skin cell culture systems that permitted assessment of the effect of connexin mimetic peptides on wound closure rates. The 3D organotypic model expressed predicted differentiation markers, such as involucrin and occludin, in the stratified layers and connexin expression profiles correlated with that found in vivo. Connexin mimetic peptides inhibited GJIC and enhanced wound-closure rates in both 2D human skin cultures of keratinocytes and fibroblasts, and in the 3D organotypic skin-equivalent system, illustrating that inhibition of gap junction activity plays an important role in wound closure events.
At low doses Gap27 was selective to Cx43 gap junctions, the primary connexin associated with wound healing, whereas a modified peptide, Gap26M, had protracted action and was an effective blocker of a variety of connexin subtypes and efficiently attenuated wound closure in keratincoytes where a number of different connexin subtypes are expressed. The connexin expression profile of human skin fibroblasts and keratinocytes pre- and post-wound closure showed that Cx43 expression was reduced at the wound edge from 3 hours post-wounding, resolving at 24 hours.
Taken together, our findings provide a sound platform for the translation of connexin mimetic peptides to therapeutic benefit.
Original languageEnglish
Publication statusPublished - 2008

Keywords

  • therapeutic benefits
  • gap junction inhibitors
  • chronic wound healing

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