RESUMEN
BACKGROUND: Combined treatment using salt water baths and artificial ultraviolet (UV) radiation (balneophototherapy, BPT) is a common therapeutic option for conditions such as psoriasis. However, it remains unknown whether pre-treatment with salt water soaks alter inflammatory and/or carcinogenic effects of UVB phototherapy. OBJECTIVES: We aimed to investigate the impact of BPT on COX-2 gene expression and apoptosis in normal and psoriatic keratinocytes. METHODS: Normal epidermis models (NEM) and psoriatic epidermis models (PEM) were treated using different salt water soaks (3% NaCl, 30% NaCl, 30% Dead Sea salt; DSS) and subsequent narrowband ultraviolet B (NB-UVB) for three consecutive days. RT-PCR was performed for cyclooxygenase 2 (COX-2), survivin, and caspase-3. RESULTS: Compared with untreated controls COX-2 mRNA was significantly increased in NB-UVB irradiated NEM and PEM. NB-UVB-exposed and non-exposed 30% NaCl and 30% DSS-treated NEM and PEM (except for NB-UVB-exposed and non-irradiated 30% DSS) showed significantly higher COX-2 mRNA when compared with controls and 3% NaCl. In NB-UVB-exposed 30% NaCl and 30% DSS-treated NEM and PEM survivin mRNA was significantly decreased when compared with controls and 3% NaCl. Compared with NB-UVB-exposed controls mRNA of caspase-3 was significantly increased in NB-UVB-exposed 30% NaCl and 30% DSS-treated PEM. CONCLUSION: Although BPT using high-concentrated salt water solutions is associated with increased epidermal COX-2 mRNA expression, apoptosis of keratinocytes is enhanced possibly due to the down-regulation of survivin mRNA expression. If confirmed in larger studies these observations have important implications for BPT efficacy as well as safety, particularly with regard to the risk of early carcinogenesis.
Asunto(s)
Balneología , Ciclooxigenasa 2/genética , Expresión Génica/efectos de los fármacos , Psoriasis/genética , Terapia Ultravioleta , Apoptosis , Caspasa 3/genética , Terapia Combinada/métodos , Epidermis/metabolismo , Humanos , Queratinocitos , Psoriasis/terapia , ARN Mensajero/metabolismo , Cloruro de Sodio/farmacología , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Epigenetics refers to functionally relevant changes in the genome other than those of DNA sequence that can lead to changes in gene expression or cellular phenotype. There is evidence that epigenetics is relevant in the pathogenesis of autoimmune diseases such as vulvar lichen sclerosus (VLS), as well as in cancer, including cutaneous squamous cell carcinoma, which is frequently associated with VLS. OBJECTIVES: To study the global methylation and hydroxymethylation status in healthy controls and VLS lesions before and after long-term ultraviolet (UV)A1 treatment. METHODS: We studied 12 controls and 10 patients with VLS who were treated with medium-dose UVA1 four times weekly for 3 months. Immunohistochemistry and mutation analyses (polymerase chain reaction) were performed for 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), isocitrate dehydrogenases (IDHs) and the ten-eleven translocation (TET)2 enzyme. RESULTS: After 3 months of treatment, 5mC was significantly increased in VLS compared with baseline and controls. However, compared with controls 5hmC levels were significantly reduced in baseline VLS, but normalized after UVA1 treatment. Compared with controls, IDH1 expression was significantly higher in both treated and baseline VLS. By contrast, IDH2 levels were significantly reduced in baseline VLS compared with controls and UVA1-treated VLS. However, gene sequencing of the IDH1, IDH2 and TET2 genes did not reveal evidence of mutations. CONCLUSIONS: VLS is associated with altered expression of IDH enzymes and aberrant hydroxymethylation, indicating an epigenetic background for the pathogenesis of VLS. UVA1 phototherapy may cause normalization of 5hmC patterns, but also global DNA hypermethylation in VLS lesions, raising concerns with respect to an increased risk of photocarcinogenesis.
Asunto(s)
Mutación/genética , Liquen Escleroso Vulvar/genética , 5-Metilcitosina/metabolismo , Metilación de ADN/genética , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Epigénesis Genética/genética , Femenino , Genes Supresores de Tumor/fisiología , Humanos , Isocitrato Deshidrogenasa/metabolismo , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/metabolismo , Terapia Ultravioleta , Liquen Escleroso Vulvar/radioterapiaRESUMEN
BACKGROUND: Polymorphic light eruption (PLE) is considered to be an autoimmune-mediated skin condition in which the normal ultraviolet (UV)-induced local immunosuppression appears to be absent, leading to recognition of photoinduced autoantigens and subsequent inflammation. OBJECTIVES: To investigate T regulatory cells (Tregs) and related immunoregulatory factors in PLE lesions and controls. METHODS: Skin biopsies were performed in 13 patients with UVA1-challenged PLE, 12 female patients with chronic discoid lupus erythematosus (CDLE) and 11 healthy controls who had exposure to UVA1. Immunohistochemistry and four-colour immunofluorescence studies were performed. RESULTS: Patients with CDLE and UVA1-exposed controls showed significantly decreased epidermal immunoreactivity for CD1a compared with patients with PLE (P = 0·0001). Four-colour immunofluorescence revealed a median percentage of CD4+CD25+FOXP3+ Tregs of 7·6% (range 3·7-13·6%) in PLE, a median of 11·7% (range 9·5-13·9%) in CDLE and a median of 3·4% (range 0-6·8%) in controls. Compared with UVA1-exposed controls, PLE and CDLE lesions showed significantly decreased transforming growth factor (TGF)-ß1 immunoreactivity in the epidermis (P = 0·0003). In PLE lesions, we observed significantly decreased interleukin (IL)-10 expression compared with CDLE (P = 0·022). In the dermis, receptor activator of nuclear factor-κB ligand (RANKL) expression was increased in UVA1-exposed controls compared with PLE and CDLE (P = 0·018). CONCLUSIONS: Similar to CDLE lesions, UVA1-challenged PLE lesions display an altered immunoregulatory network, as indicated by decreased epidermal or dermal expression of TGF-ß1, IL-10 and RANKL, and a relatively low number of Tregs, particularly when compared with other inflammatory skin conditions reported in the literature.
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Lupus Eritematoso Discoide/inmunología , Trastornos por Fotosensibilidad/inmunología , Linfocitos T Reguladores/inmunología , Rayos Ultravioleta , Adulto , Estudios de Casos y Controles , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Tolerancia Inmunológica/inmunología , Inmunohistoquímica , Interleucina-10/metabolismo , Ligando RANK/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The role of transforming growth factor-ß1 (TGFß1) and Smad signalling has not been established in psoriasis treatment. We aimed to investigate the effect of combined treatment with salt water soaks and ultraviolet radiation on the expression of TGFß1/Smad signalling proteins in a psoriatic model. We studied mRNA expression (real-time RT-PCR) of TGFß1, TGFß receptor type I (TGFßRI), Smad2, Smad3, Smad4, Smad7, minichromosome maintenance protein 7, and involucrin in normal as well as psoriatic epidermis models (PEM) which were treated for three consecutive days with differently concentrated salt water solutions [(3% NaCl; 30% NaCl, 30% Dead Sea salt water (DSSW)] and subsequent narrowband ultraviolet B (NB-UVB). In PEM, TGFß1 and Smad3 was significantly increased as compared to normal epidermis models. By contrast, TGFßRI mRNA was significantly decreased in PEM. Significant increase of mRNA levels of TGFß1, TGFßRI, Smad2 and Smad3 was predominantly observed in non-irradiated and irradiated PEM pre-treated with 30% NaCl and/or DSSW which was paralleled by increase of involucrin mRNA. In PEM pre-treated with DSSW, TGFßRI, Smad2, Smad3, Smad4, and Smad7 mRNA was significantly higher in irradiated PEM when compared to non-irradiated samples. It has been shown that TGFß1/Smad signalling is altered in a psoriatic model and may play a role in the mode of action of salt water soaks and NB-UVB phototherapy of psoriasis.
Asunto(s)
Psoriasis/terapia , Proteínas Smad/metabolismo , Cloruro de Sodio/uso terapéutico , Factor de Crecimiento Transformador beta1/metabolismo , Terapia Ultravioleta , Línea Celular , Epidermis/metabolismo , Humanos , Queratinocitos/metabolismo , Componente 7 del Complejo de Mantenimiento de Minicromosoma/biosíntesis , Componente 7 del Complejo de Mantenimiento de Minicromosoma/genética , Componente 7 del Complejo de Mantenimiento de Minicromosoma/metabolismo , Precursores de Proteínas/biosíntesis , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Psoriasis/metabolismo , ARN Mensajero/biosíntesis , Receptores de Factores de Crecimiento Transformadores beta/biosíntesis , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteína Smad2/biosíntesis , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/biosíntesis , Proteína smad3/genética , Proteína smad3/metabolismo , Proteína Smad4/biosíntesis , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína smad7/biosíntesis , Proteína smad7/genética , Proteína smad7/metabolismo , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
BACKGROUND: Photodynamic therapy (PDT) and laser ablation (LA) are frequently used treatment options for multiple actinic keratoses (AK), yet they have not been compared head to head. OBJECTIVES: To compare PDT and carbon dioxide (CO(2) ) LA in the management of multiple AK using objective and subjective outcome measures. METHODS: A single-centre, randomized, two-treatment half-side comparative study of PDT vs. CO(2) LA was performed. Patients with at least four bilateral (e.g., scalp, forearms) AK were included. The primary outcome measure was the reduction of AK 3 months (v3) after therapy. Secondary outcome measures included the reduction of AK 4 weeks (v2) after therapy, decrease of epidermal p53 and Ki-67 protein expression, micromorphological changes as assessed by optical coherence tomography (OCT) in vivo, and investigators' and patients' satisfaction scoring. RESULTS: In total, 20 patients (18 men and 2 women) completed the study. Both treatments reduced AK quantity significantly. On v3, relative reduction of AK quantity was significantly higher following PDT (P = 0·0362). Ki-67 and p53 protein expression was reduced significantly from baseline (Ki-67, median 49·5%; p53, median 64·8%) to v2 by both procedures (PDT, median 18·5%, P < 0·0001; LA, median 16·2%, P < 0·0001). AK features as assessed by OCT imaging were also significantly reduced by both procedures. The investigators and patients rated the side-effects and inconveniences of PDT as more severe, but both overall preferred PDT due to the superior clinical outcome. CONCLUSIONS: CO(2) LA and PDT are both effective therapy options for multiple AK, yet PDT seems to be superior in terms of AK reduction and participants' and investigators' overall satisfaction.
Asunto(s)
Ácido Aminolevulínico/uso terapéutico , Queratosis Actínica/terapia , Terapia por Láser/métodos , Láseres de Gas/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Anciano , Anciano de 80 o más Años , Epidermis/metabolismo , Femenino , Humanos , Queratosis Actínica/tratamiento farmacológico , Queratosis Actínica/patología , Queratosis Actínica/cirugía , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND/AIMS: The exact mechanisms of action of balneophototherapy are incompletely understood. We aimed to investigate the effect of salt water soaks on ultraviolet (UV) transmission and the expression of molecular parameters of psoriasis. METHODS: We studied UV transmission and the expression of antimicrobial peptides and skin-derived antileukoproteinase (SKALP/elafin) in psoriatic epidermis equivalents which were pretreated with tap water and differently concentrated salt water solutions. Moreover, we performed in vivo phototoxicity tests in healthy subjects. RESULTS: Highly concentrated salt water soaks significantly increase UV transmission through psoriatic epidermis equivalents, in particular within the wavelength range of 305- 360 nm. In vivo tests revealed increased photosensitivity following highly concentrated salt water baths. A significant decrease in human ß-defensin-2 (hBD-2) and SKALP/elafin is observed after highly concentrated NaCl soaks. CONCLUSION: An increase in UV transmission following highly concentrated salt water soaks likely causes enhanced UV gain within the viable epidermis. Moreover, our data indicate that salt water soaks seem to influence the protein profiles of hBD-2 and SKALP/elafin.