title: Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration.
abstract: Experimental downregulation of connexin43 (Cx43) expression at skin wound sites appears to markedly improve the rate and quality of healing, but the underlying mechanisms are currently unknown. Here, we have compared physiological and cell biological aspects of the repair process with and without Cx43 antisense oligodeoxynucleotide treatment. Treated wounds exhibited accelerated skin healing with significantly increased keratinocyte and fibroblast proliferation and migration. In vitro knockdown of Cx43 in a fibroblast wound-healing model also resulted in significantly faster healing, associated with increased mRNA for TGF-beta1, and collagen alpha1 and general collagen content at the wound site. Treated wounds showed enhanced formation of granulation tissue and maturation with more rapid angiogenesis, myofibroblast differentiation and wound contraction appeared to be advanced by 2-3 days. Recruitment of both neutrophils and macrophages was markedly reduced within treated wounds, concomitant with reduced leukocyte infiltration. In turn, mRNA levels of CC chemokine ligand 2 and TNF-alpha were reduced in the treated wound. These data suggest that, by reducing Cx43 protein with Cx43-specific antisense oligodeoxynucleotides at wound sites early in the skin healing process repair is enhanced, at least in part, by accelerating cell migration and proliferation, and by attenuating inflammation and the additional damage it can cause.
authors.affiliation: Department of Physiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Mori
authors.forename: Kieran T
authors.initials: KT
authors.lastname: Power
authors.forename: Chiuhui Mary
authors.initials: CM
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.forename: David L
authors.initials: DL
authors.lastname: Becker
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D017629:Gap Junctions / Q000378:metabolism; D006097:Granulation Tissue / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
chemical_list: D018031:Connexin 43; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D003094:Collagen