The Journal of investigative dermatology
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J. Invest. Dermatol. · Jan 2000
Enhanced vascularization of cultured skin substitutes genetically modified to overexpress vascular endothelial growth factor.
Cultured skin substitutes have been used as adjunctive therapies in the treatment of burns and chronic wounds, but they are limited by lack of a vascular plexus. This deficiency leads to greater time for vascularization compared with native skin autografts and contributes to graft failure. Genetic modification of cultured skin substitutes to enhance vascularization could hypothetically lead to improved wound healing. ⋯ Vascular endothelial growth factor-modified and control cultured skin substitutes were grafted to full-thickness wounds on athymic mice, and elevated vascular endothelial growth factor mRNA expression was detected in the modified grafts for at least 2 wk after surgery. Vascular endothelial growth factor-modified grafts exhibited increased numbers of dermal blood vessels and decreased time to vascularization compared with controls. These results indicate that genetic modification of keratinocytes in cultured skin substitutes can lead to increased vascular endothelial growth factor expression, which could prospectively improve vascularization of cultured skin substitutes for wound healing applications.
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J. Invest. Dermatol. · Nov 1999
Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions.
Erythema multiforme follows administration of several drugs or infection with various agents, including herpes simplex virus, a syndrome designated herpes simplex virus associated erythema multiforme. Lesional skin from 21 of 26 (81%) herpes simplex virus associated erythema multiforme patients was positive for herpes simplex virus gene expression as evidenced by reverse transcriptase-polymerase chain reaction with primers for DNA polymerase and/or immunohistochemistry with DNA polymerase antibody. Reverse transcriptase-polymerase chain reaction and immunohistochemistry studies indicated that herpes simplex virus associated erythema multiforme lesional skin from 16 of 21 (76%) DNA polymerase positive herpes simplex virus associated erythema multiforme patients was also positive for interferon-gamma, a product of T cells involved in delayed-type hypersensitivity (p < 0. 0001 by Pearson correlation coefficient). ⋯ Staining was also seen in keratinocytes from herpes simplex virus lesions [five of five (100%)], but not in normal skin. By contrast, staining with antibody to tumor necrosis factor-alpha, another pro-inflammatory cytokine, was seen in seven of 11 (64%) drug-induced erythema multiforme patients, but not in herpes simplex virus or herpes simplex virus associated erythema multiforme patients, and lesional keratinocytes from drug-induced erythema multiforme patients were negative for transforming growth factor-beta and cyclin-dependent kinase inhibitor waf. We interpret the data to indicate that herpes simplex virus associated erythema multiforme pathology includes a delayed-type hypersensitivity component and is mechanistically distinct from drug-induced erythema multiforme.
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J. Invest. Dermatol. · Oct 1999
The CXCR3 activating chemokines IP-10, Mig, and IP-9 are expressed in allergic but not in irritant patch test reactions.
Differentiation between allergic and irritant contact dermatitis reactions is difficult, as both inflammatory diseases are clinically, histologically, and immunohistologically very similar. Previous studies in mice revealed that the chemokine IP-10 is exclusively expressed in allergic contact dermatitis reactions. In the present study, we investigated whether the mRNA expression of IP-10 and the related CXCR3 activating chemokines, Mig and IP-9 are also differentially expressed in human allergic contact dermatitis and irritant contact dermatitis reactions. ⋯ ICAM-1 expression by keratinocytes was only found in allergic contact dermatitis reactions and correlated with chemokine expression. Moreover, up to 50% of the infiltrating cells in allergic contact dermatitis expressed CXCR3, in contrast to only 20% in irritant contact dermatitis reactions. In conclusion, we have demonstrated differences in chemokine expression between allergic contact dermatitis and irritant contact dermatitis reactions, which might reflect different regulatory mechanisms operating in these diseases and may be an important clue for differentiation between allergic contact dermatitis and irritant contact dermatitis reactions.
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J. Invest. Dermatol. · Sep 1999
Percutaneous penetration of local anesthetic bases: pharmacodynamic measurements.
Local anesthetics do not penetrate readily through human skin if applied in their salt form; however, if applied in their base form various effects may be observed, such as a decrease in pricking pain and a change in burning, itch, and thermal sensations. These effects occur after skin penetration and may be attributed to the action of the anesthetics on nociceptors and thermoreceptors, i.e., on C and Adelta nerve fiber respectively. As there is little known about the time course of the pharmacodynamic response of cutaneously applied local anesthetic bases, this study was conducted to characterize various local anesthetics pharmacodynamically by measuring thermal thresholds over time with a thermal sensory analyzer. ⋯ From the response versus time profiles of all eight study subjects various response parameters were obtained: only the cold sensation parameters proved suitable for characterization of the local anesthetics, possibly because cold receptors are located in the epidermis and can easily be reached. Lag times of onset are short and the maximum anesthetic effect is reached within 2-3 h. Cold sensation parameters correlate linearly with the solubility of the local anesthetic bases in medium chain triglycerides and with the drug flux of 50% saturation, indicating that medium chain triglycerides may have similar properties with regard to the local anesthetics solubility as the stratum corneum lipids.
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The aim of this study was to compare local blood flow in psoriatic plaques before and after provocations known to alter cutaneous vascular resistance, in order to determine whether plaque hyperemia is caused by a failure of normal vascular control mechanisms. Cutaneous blood flow was recorded using a laser Doppler flowmeter over plaque skin (plaque site) and clinically normal skin (nonplaque site) on the opposite arm, at least 5 cm away from the nearest plaque. It is important to note that most of the laser Doppler signal comes from the subpapillary plexus of the skin and only a small portion (2%-10%) is produced by capillary blood flow. ⋯ Tests of vasodilatation indicated that, although basal flux is high in plaque compared with nonplaque skin, arterioles supplying plaque skin can dilate further, i.e., lesional arterioles are not normally maximally dilated but have a basal constrictor tone. Interestingly, the red cell flux at maximum dilatation in nonplaque skin is less than even the basal flux in plaque skin. This means that in plaque skin either there are more arterioles than in nonplaque skin, or there is chronic, structural widening of the existing arterioles in plaque skin.