The Journal of investigative dermatology
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J. Invest. Dermatol. · Aug 2008
Hyperbaric oxygen attenuates apoptosis and decreases inflammation in an ischemic wound model.
The molecular mechanisms whereby hyperbaric oxygen (HBO) improves ischemic wound healing remain elusive. In this study, a rat model of wound ischemia was used to test the hypothesis that HBO enhances wound healing by modulating hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Male Sprague-Dawley rats underwent creation of a previously validated ischemic flap. ⋯ DNA fragmentation was abolished and the number of TUNEL-positive cells was reduced compared to the other groups. Vascular endothelial growth factor, cyclooxygenase-2, and neutrophil infiltration were reduced in ischemic wounds treated with HBO. These results indicate that HBO improves ischemic wound healing by downregulation of HIF-1alpha and subsequent target gene expression with attenuation of cell apoptosis and reduction of inflammation.
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J. Invest. Dermatol. · Aug 2008
Profibrinolytic effects of metalloproteinases during skin wound healing in the absence of plasminogen.
Genetic ablation of plasminogen (Plg) and pharmacological inhibition of metalloproteinase activity by galardin delay skin wound healing in mice, whereas the combined inhibition of these two enzyme systems completely prevents healing. In this study, the impact of plasmin and metalloproteinases as profibrinolytic enzymes has been investigated by comparing skin wound healing in the absence and presence of fibrin. Plg deficiency impairs skin wound healing kinetics, but this delay is only partially restored in the absence of fibrin. ⋯ The profibrinolytic role of metalloproteinases is revealed by the finding that lack of fibrin partially restores the otherwise arrested healing of Plg-deficient wounds after metalloproteinase inhibition. In conclusion, the residual impairment of skin wound healing in the absence of fibrin suggests the existence of a fibrin-independent substrate(s) for plasmin and metalloproteinases. Furthermore, these in vivo data reveal that galardin-sensitive metalloproteinases mediate compensatory fibrinolysis to facilitate wound healing in the absence of plasmin.
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J. Invest. Dermatol. · Feb 2008
CD158K/KIR3DL2 transcript detection in lesional skin of patients with erythroderma is a tool for the diagnosis of Sézary syndrome.
The distinction between Sézary syndrome (SS) and benign erythrodermic inflammatory diseases (EID) is difficult to make both clinically and on skin biopsies, since histomorphology can provide nonspecific results. New markers of circulating malignant Sézary cells have been recently described, especially CD158k/KIR3DL2 and T-plastin, but it has not been yet determined whether they could help in the diagnosis of erythroderma in skin samples. In this study, 13 frozen skin specimens from 10 SS patients and 26 from EID were analyzed for CD158k/KIR3DL2 expression using immunohistochemistry with AZ158 mAb, which also recognizes the monomeric CD158e/KIR3DL1 receptor. ⋯ Therefore in all samples disclosing a significant staining with AZ158 mAb, CD158k/KIR3DL2, CD158e/KIR3DL1 and T-plastin mRNA expression were analyzed on the same skin specimen using conventional and/or quantitative real-time reverse transcription (RT)-PCR. Interestingly, only CD158k/KIR3DL2 transcripts were found to be significantly overexpressed in skin biopsies from patients with SS (P<0.0001), including when normalization to CD3 expression was achieved (P=0.0003). In light of these findings, CD158k/KIR3DL2 transcripts appear to be a unique molecular marker of SS in skin samples, allowing differential diagnosis with benign EID in routine practice.
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J. Invest. Dermatol. · Aug 2007
A mouse mutation in the 12R-lipoxygenase, Alox12b, disrupts formation of the epidermal permeability barrier.
Nonbullous congenital ichthyosiform erythroderma (NCIE) is a nonsyndromic form of autosomal recessive congenital ichthyosis characterized by hyperkeratosis and a disruption in the epidermal permeability barrier. Identification of mutations in two lipoxygenases (LOXs), ALOX12B (12R-LOX) and ALOXE3 (eLOX3), and further functional studies implicate ALOX12B and ALOXE3 in the etiology of NCIE. Here, we report a mutation in Alox12b in the recessive ethylnitrosurea-induced mouse mutant, mummy (Alox12b(mmy-Bei)). mummy mutants have red, scaly skin and die perinatally. ⋯ Sequencing of all three genes identified a nonsense mutation in the catalytic domain of Alox12b. We demonstrate that mummy mutants have a disrupted epidermal permeability barrier and that the nonsense mutation in mummy abolishes the enzyme activity of 12R-LOX. The mummy mutant provides a mouse model for LOX-mediated NCIE and is the first described mouse mutant affecting epidermal barrier formation identified by forward genetics.