To gain insight into the molecular mechanisms underlying cutaneous wound repair, we performed a large scale screen to identify novel injury-regulated genes. Here we show a strong up-regulation of the RNA and protein levels of the two Ca 2؉ -binding proteins S100A8 and S100A9 in the hyperthickened epidermis of acute murine and human wounds and of human ulcers. Furthermore, both genes were expressed by inflammatory cells in the wound. The increased expression of S100A8 and S100A9 in wound keratinocytes is most likely related to the activated state of the keratinocytes and not secondary to the inflammation of the skin, since we also found up-regulation of S100A8 and S100A9 in the epidermis of activin-overexpressing mice, which develop a hyperproliferative and abnormally differentiated epidermis in the absence of inflammation. Furthermore, S100A8 and S100A9 expression was found to be associated with partially differentiated keratinocytes in vitro. Using confocal microscopy, both proteins were shown to be at least partially associated with the keratin cytoskeleton. In addition, cultured keratinocytes efficiently secreted the S100A8/A9 dimer. These results together with previously published data suggest that S100A8 and S100A9 are novel players in wound repair, where they might be involved in the reorganization of the keratin cytoskeleton in the wounded epidermis, in the chemoattraction of inflammatory cells, and/or in the defense against microorganisms.After cutaneous injury, a series of biological events takes place that aims at the reconstruction of the damaged skin. Among them are the migration, proliferation, and differentiation of inflammatory, epithelial, and mesenchymal cells. These cells exert specific functions in a temporally and spatially coordinated manner such as the removal of irreversibly destructed tissue, the deposition of new extracellular matrix, and the reestablishment of the cutaneous barrier (1, 2). These processes are well described at the histological level, but little is known about their molecular basis.To gain insight into the molecular mechanisms that underlie the repair process, we performed a large scale subtractive hybridization screen to systematically identify genes that are differentially expressed in injured compared with normal skin. To minimize the risk of detecting differences in gene expression levels due to changes in cellular composition rather than to transcriptional regulation, we compared normal skin with early (24 h) wounds, because only minor changes in cell type composition occur during the initial wound healing period.One of the cDNA clones that we obtained encodes the murine S100A8 protein (also known as calgranulin A, MRP8, leukocyte protein L1, or cytokine CP-10). S100 proteins are intracellular Ca 2ϩ -binding and Ca 2ϩ -modulated proteins that form antiparallel noncovalently linked dimers in solution and play a role in various Ca 2ϩ -mediated cellular functions including cell growth and differentiation, energy metabolism, cytoskeletalmembrane interactions; some of th...
Negative co‐factor 2 (NC2) regulates transcription of the class II genes through binding to TFIID and inhibition of pre‐initiation complex formation. We have isolated and cloned NC2, and investigated the molecular mechanism underlying repression of transcription. NC2 consists of two subunits, termed NC2alpha and NC2beta, the latter of which is identical to Dr1. The NC2 subunits dimerize and bind to TATA binding protein (TBP)‐promoter complexes via histone fold domains of the H2A‐H2B type. Repression of basal transcription requires the histone fold and carboxy‐terminal domains of the NC2 subunits. Several mechanisms probably contribute to transcriptional repression. Binding of NC2 inhibits association of TFIIB with TBP‐promoter complexes. NC2 binds directly to DNA, and binding of NC2 to TBP‐promoter complexes affects the conformation of DNA, which could be one cause for the inhibition of TFIIB. In addition, multimerization of repressor‐TBP complexes on DNA might inhibit the assembly of the pre‐initiation complex. We suggest that binding of the repressor to TRP‐promoter complexes establishes a mechanism that controls the rate of transcription by RNA polymerase II.
Recently, we demonstrated a strong upregulation of activin expression after skin injury. Furthermore, overexpression of this transforming growth factor b family member in the skin of transgenic mice caused dermal ®brosis, epidermal hyperthickening and enhanced wound repair. However, the role of endogenous activin in wound healing has not been determined. To address this question we overexpressed the soluble activin antagonist follistatin in the epidermis of transgenic mice. These animals were born with open eyes, and the adult mice had larger ears, longer tails and reduced body weight compared with nontransgenic littermates. Their skin was characterized by a mild dermal and epidermal atrophy. After injury, a severe delay in wound healing was observed. In particular, granulation tissue formation was signi®cantly reduced, leading to a major reduction in wound breaking strength. The wounds, however, ®nally healed, and the resulting scar area was smaller than in control animals. These results implicate an important function of endogenous activin in the control of wound repair and scar formation.
SummaryBackgroundOxidized cellulose is a well known and widely used surgical hemostat. It is available in many forms, but manufactured using either a nonregenerated or regenerated process.ObjectiveThis study compares the fiber structure, pH in solution, bactericidal effectiveness, and hemostatic effectiveness of an oxidized nonregenerated cellulose (ONRC; Traumastem®) and an oxidized regenerated cellulose (ORC; Surgicel® Original).MethodsIn vitro, fiber structures were compared using scanning electron microscopy, pH of phosphate buffer solution (PBS) and human plasma were measured after each cellulose was submerged, and bactericidal effect was measured by plating each cellulose with four bacteria. In vivo, time to hemostasis and hemostatic success were compared using a general surgery nonheparinized porcine liver abrasion model and a peripheral vascular surgery heparinized leporine femoral vessel bleeding model.ResultsUltrastructure of ONRC fiber is frayed, while ORC is smooth. ORC pH is statistically more acidic than ONRC in PBS, but equal in plasma. No difference in bactericidal effectiveness was observed. In vivo, ONRC provided superior time to hemostasis relative to ORC (211.2 vs 384.6 s, N = 60/group) in the general surgery model; and superior hemostatic success relative to ORC at 30 (60 vs. 15 %; OR: 13.5; 95 % CI: 3.72–49.1, N = 40/group), 60 (85 vs. 37.5 %; OR: 12.3; 95 % CI: 3.66–41.6), and 90 s (97.5 vs 70.0 %; OR: 21.1, 95 % CI: 2.28–195.9) in the peripheral vascular model.ConclusionONRC provides superior hemostasis and equivalent bactericidal effectiveness relative to ORC, which is likely due to its fiber structure than acidity.
Cardiac ankyrin repeat protein (CARP) was identified by subtractive hybridization as one of a group of genes that are rapidly modulated by acute wounding of mouse skin. Quantitative RT-PCR showed that CARP was strongly induced during the first day after wounding (157.1-fold), and the high level persisted for up to 14 days. Immunohistochemistry and in situ hybridization revealed that CARP was expressed in skeletal muscle, vessel wall, hair follicle, inflammatory cells, and epidermis in the wound area. To examine the effects of CARP on wound healing, we developed an adenoviral CARP vector to treat subcutaneously implanted sponges in either rats or
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