Simulated UV daylight is a relevant new tool for daily photoprotection studies.
Solar radiation causes immunosuppression that contributes to skin cancer growth. Photoprotective strategies initially focused on the more erythemogenic ultraviolet B. More recently, the relationship of ultraviolet A and skin cancer has received increased attention. We hypothesized that if ultraviolet A contributes significantly to human ultraviolet-induced immune suppression, then increased ultraviolet A filtration by a sunscreen would better protect the immune system during ultraviolet exposure. Two hundred and eleven volunteers were randomized into study groups and received solar-simulated radiation, ranging from 0 to 2 minimum erythema dose, on gluteal skin, with or without sunscreen, 48 h prior to sensitization with dinitrochlorobenzene. Contact hypersensitivity response was evaluated by measuring the increase in skin fold thickness of five graded dinitrochlorobenzene challenge sites on the arm, 2 wk after sensitization. Clinical scoring using the North American Contact Dermatitis Group method was also performed. Solar-simulated radiation dose-response curves were generated and immune protection factor was calculated using a nonlinear regression model. Significance of immune protection between study groups was determined with the Mann-Whitney-Wilcoxon exact test. The sunscreen with high ultraviolet A absorption (ultraviolet A protection factor of 10, based on the in vivo persistent pigment darkening method) and a labeled sun protection factor of 15 demonstrated better immune protection than the product that had a low ultraviolet A absorption (ultraviolet A protection factor of 2) and a labeled sun protection factor of 15. Nonlinear regression analysis based on skin fold thickness increase revealed that the high ultraviolet A protection factor sunscreen had an immune protection factor of 50, more than three times its sun protection factor, whereas the low ultraviolet A protection factor sunscreen had an immune protection factor of 15, which was equal to its labeled sun protection factor. This study demonstrates that ultraviolet A contributes greatly to human immune suppression and that a broad-spectrum sunscreen with high ultraviolet A filtering capacity results in immune protection that exceeds erythema protection. These results show that high ultraviolet A protection is required to protect against ultraviolet-induced damage to cutaneous immunity.
All-trans retinoic acid (RA) has been shown to enhance subepidermal repair in photoaged hairless mice. The current study assesses the effects of RA on the glycosaminoglycan (GAG) content in irradiated and nonirradiated mouse skin. Mice were exposed to ultraviolet B (UVB) for 10 wk, after which they were treated either with 0.05% RA or with an ethanolpolyethylene glycol 400 vehicle three times a week for 10 or 20 wk. When assessed at the end of 10 wk of UVB irradiation, the GAG content had doubled, without a change in the hyaluronic acid (HA) to dermatan sulfate (DS) ratio. When irradiation was discontinued, the GAG content decreased progressively until the end of the experimental period. This decline was totally inhibited by RA treatment and could be ascribed to a marked increase in hyaluronic acid (78%), whereas no significant change in DS was observed. In nonirradiated skin, however, topical RA increased GAG levels mainly by a pronounced increase in the content (50%) and the synthesis (40%) of DS. In untreated mice, the HA/DS ratio decreased significantly with age in both irradiated and nonirradiated mice. Interestingly, RA maintained this ratio only in animals exposed to UVB. In addition, there was a marked stimulation in the heparin content, up to approximately 20-fold, after irradiation, whereas the amount of heparin in both irradiated and nonirradiated skin increased about 2- to 3-fold with RA treatment. In summary, the alterations induced in HA and DS contents in irradiated and nonirradiated skin indicate the specificity of the RA-induced effects for the various GAGs.
Environmental insults on the skin induce biologic responses through the modulation of expression of genes implicated in different cell functions. The aim of this study was to investigate the modulation of gene expression profile in human epidermis in vivo following different stresses. We determined the modulations of gene expression using cDNA macroarray in the epidermis of 28 healthy volunteers, following mild and physiologic insults, including: (1), tape stripping; (2) application of 10% sodium dodecyl sulfate; (3) daily application of vaseline; and (4), exposure to one minimal erythema dose of solar-simulated radiation. The analysis was performed 19 h after treatment. The reverse transcription-polymerase chain reaction method was used to confirm our results. We showed that: (1) the intensity of gene modulation was variable among the volunteers following the same skin stress; (2) the nature and intensity of skin treatment modified the pattern of gene expression; and (3) some genes were modulated only by specific stress, some others are modulated irrespective of the stress. GADD45, Bax, SAS, and granulocyte chemotactic protein-2 were overexpressed exclusively following solar-simulated radiation, whereas tape stripping led to the modulation of genes implicated in different pathways (inflammation, cell proliferation, cell differentiation, detoxification, etc.). Concerning common gene modulation, MRP8 and MRP14 were highly upregulated in human skin epidermis after solar-simulated radiation, vaseline application or tape stripping, and to a lower extent after sodium dodecyl sulfate. Such upregulation of the MRP 8/14 genes was confirmed at the protein level in an ex-vivo skin culture model following tape stripping and solar-simulated radiation. Together, these results suggest that MRP8 and MRP14 may be general, yet highly sensitive, markers for a great variety of skin stresses and that they are implicated in several epidermal repair pathways.
We investigated skin lesions induced in hairless SKH:HR1 mice by chronic exposure to a solar ultraviolet light (UV) simulator for alterations of the p53 gene in conserved domains. Mutations of exons 5-8 of the p53 gene in skin lesions were screened in 31 benign skin lesions (hyperplasias), 25 precancerous skin lesions (keratoacanthomas), and 25 malignant skin lesions (squamous cell carcinomas; SCC) by polymerase chain reaction-single-strand conformation polymorphism analysis. Most of the mutations occurred at dipyrimidine sequences located on the nontranscribed strand; the most frequent modifications were C-->T transitions (77%) and CC-->TT tandem mutations (5%); the latter are considered the UV fingerprint. p53 mutations were detected in 3% of the hyperplasias, 12% of the keratoacanthomas, and 52% of the SCCs. Hence, the high frequency of p53 mutations in SCCs compared with keratoacanthomas induced by a solar UV simulator suggested that, in our study, p53 mutations probably occurred as a late event in the skin carcinogenesis progression of SCC. Interestingly, the level of CC-->TT tandem mutations in the SCCs (5%) was similar to that found in SCCs induced in hairless mice by UVB alone. p53 protein was also detected in the different types of skin lesions by immunohistochemical analysis. Thus, our data from hairless mouse skin tumors induced by a solar UV simulator confirmed the major role of UVB-induced DNA damage in skin carcinogenesis and suggested that UVA plays a minor role in bringing about p53 alterations.
In this study, we investigated whether the spectrum of p53 mutations in skin tumors induced in hairless SKH‐hr1 mice by a solar simulator (290–400 nm) are similar to those found in skin tumors induced in C3H mice by UV radiation from unfiltered (250–400 nm) and Kodacelfiltered (290–400 nm) FS40 sunlamps. Analysis of tumor DNA for p53 mutations revealed that 14 of 16 (87.5%) SkH‐hr1 skin tumors induced by the solar simulator contained mutations. Single C → T transitions at dipyrimidine sequences located on the nontranscribed DNA strand were the most predominant type of p53 mutation. Remarkably, 52% of all p53 mutations in solar simulator‐induced SKH‐hr1 skin tumors occurred at codon 270, which is also a hotspot in C3H skin tumors induced by unfiltered and Kodacel‐filtered FS40 sunlamps. However, T → G transversions, which are hallmarks of UVA‐induced mutations, were not detected in any of the solar simulator‐induced skin tumors analyzed. These results demonstrate that the p53 mutation spectra seen in solar simulator‐induced SKH‐hr1 skin tumors are similar to those present in unfiltered and Kodacel‐filtered FS40 sunlamp‐induced C3H skin tumors. In addition, our data indicate that the UVA present in solar simulator radiation does not play a role in the induction of p53 mutations that contribute to skin cancer development.
Two double-blind studies versus vehicle were carried out to investigate the effects of a topically applied retinol plus vitamin C combination on epidermal and dermal compartments of aged or photoaged human skin. The two studies were performed on postmenopausal women who were selected for treatment based on the mild level of elastosis of their facial skin. At completion of treatment, skin biopsies were collected and processed for classical histology and immunohistochemistry. In the first study (aged skin), 8 volunteers applied the retinol- and vitamin C-containing preparation on the ventral side of one elbow and the vehicle on the other elbow twice daily for 3 months. After the 3-month treatment we observed histological changes mainly within the epidermis. The stratum corneum was thinner with a compact pattern, whereas the epidermal proliferation increased, resulting in a thickening of the viable epidermis. Moreover, the interdigitation index was increased. In the second study (photoaged skin), 11 volunteers were divided in two groups; one applied the retinol- and vitamin C-containing preparation and the other one the vehicle on their face twice daily for 6 months. Facial skin samples presented histologic hallmarks of photoaging, i.e. accumulation of elastotic material in the papillary dermis. After the 6-month topical treatment, the observed histological changes were mainly concentrated at the dermal level. Both treated and control groups showed the same distribution pattern of type I procollagen, however, the high level of type III procollagen originally observed in photoaged skin was reduced in the retinol- and vitamin C-treated group, resulting in a lower type III-to-type I procollagen ratio. Furthermore, a wide band of eosinophilic material just beneath the epidermis, devoid of oxytalan fibers and forming the ‘grenz zone’, appeared more frequently and was larger in the retinol- and vitamin C-treated group. In conclusion, our results show that repeated topical application of a preparation containing both retinol and vitamin C is able to reverse, at least in part, skin changes induced by both chronologic aging and photoaging.
In this study, we investigated whether the spectrum of p53 mutations in skin tumors induced in hairless SKH-hr1 mice by a solar simulator (290-400 nm) are similar to those found in skin tumors induced in C3H mice by UV radiation from unfiltered (250-400 nm) and Kodacel-filtered (290-400 nm) FS40 sunlamps. Analysis of tumor DNA for p53 mutations revealed that 14 of 16 (87.5%) SkH-hr1 skin tumors induced by the solar simulator contained mutations. Single C-->T transitions at dipyrimidine sequences located on the nontranscribed DNA strand were the most predominant type of p53 mutation. Remarkably, 52% of all p53 mutations in solar simulator-induced SKH-hr1 skin tumors occurred at codon 270, which is also a hotspot in C3H skin tumors induced by unfiltered and Kodacel-filtered FS40 sunlamps. However, T-->G transversions, which are hallmarks of UVA-induced mutations, were not detected in any of the solar simulator-induced skin tumors analyzed. These results demonstrate that the p53 mutation spectra seen in solar simulator-induced SKH-hr1 skin tumors are similar to those present in -unfiltered and Kodacel-filtered FS40 sunlamp-induced C3H skin tumors. In addition, our data indicate that the UVA present in solar simulator radiation does not play a role in the induction of p53 mutations that contribute to skin cancer development.
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