title: Alteration of Smad3 signaling in ischemic rabbit dermal ulcer wounds.
abstract: Impaired reepithelialization is a hallmark of chronic, ischemic wounds; however, the pathogenesis of the delayed reepithelialization in these wounds remains poorly understood. Transforming growth factor beta is involved in both the normal and hypoxic wound-healing response and exogenous overexpression of Smad3, which has been known to accelerate reepithelialization. Recently, it was shown in the rabbit ear dermal ulcer model that Ad-Smad3 injection enhanced reepithelialization and granulation tissue formation suggesting a positive effect of Smad3 on wound healing. However, little is known about the role of Smad3 in the ischemic wound healing process. In this study, we examined the effect of Smad3 in an ischemic wound model. Ad-Smad3 or Ad-LacZ (10(8) pfu/wound) was injected into either ear of white New Zealand rabbits. Twenty-four hours later, these ears were rendered ischemic using an established model, and four 7 mm full-thickness punch wounds were made on each ear. Histological evaluation showed a significant increase in reepithelialization parameters in Ad-Smad3-transfected wounds (p<0.01). In contrast, granulation tissue parameters were not affected by Smad3 in ischemia. Smad4 and Smad7 mRNA-expression was not affected by Smad3 overexpression. Connective tissue growth factor protein was up-regulated under ischemic conditions but was unaffected by Smad3 transfection in both ischemic and nonischemic wounds. Our results suggest an enhancing effect of Smad3 on reepithelialization in an ischemic wound model that, in turn, might provide novel therapeutic options. Furthermore, the lack of alteration of Smad-dependent intermediates by Smad3 overexpression suggests the activation of Smad-independent pathways in ischemia.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Wound Healing Research Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kloeters
authors.forename: Sheng-Xian
authors.initials: SX
authors.lastname: Jia
authors.forename: Nakshatra
authors.initials: N
authors.lastname: Roy
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Schultz
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Leinfellner
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mustoe
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020405:Dermis / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D007763:Lac Operon / Q000235:genetics; D011817:Rabbits; D015398:Signal Transduction; D012883:Skin Ulcer / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein; D051906:Smad7 Protein; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D051900:Smad3 Protein; D051901:Smad4 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta