RESUMEN
Systemic sclerosis (SSc) is an immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy with poor prognosis. Dangui Huoxue Preparation (DHP) is a clinically effective traditional Chinese herbal formula for the treatment of SSc in the hospital. This study aims to investigate the therapeutic effects and underlying molecular mechanisms of DHP in the treatment of SSc. SSc mice models are induced by bleomycin (BLM). Tissues of DHP group, normal control group, and positive control drug Sanqi Tongshu Capsule (STC) group are collected for inflammation, fibrosis, and vasculopathy. Also, the human dermal fibroblasts (HDF) stimulated with TGF-ß1 are analyzed for in vitro study. The expression levels of MCP-1, IFN-γ, IL-1ß, IL-10, Fizz1, iNOS, and IL12p40, and the mRNA levels of Col1a1, Col1a2, Col3a1, and Col5a1 are significantly decreased in all DHP groups and STC group compare with those in the BLM group. The main drug of DHP inhibits the proliferation and migration of HDF, reduces Ctgf, Itgb3, Itgb5 expression, and also inhibits the Smad3 pathway. In conclusion, DHP can ameliorate SSc skin inflammation, fibrosis, and vasculopathy, possibly suppressing the TGF-ß1/Smad3 signaling pathway through extracellular and intracellular mechanisms.
Asunto(s)
Esclerodermia Sistémica , Factor de Crecimiento Transformador beta1 , Humanos , Animales , Ratones , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/efectos adversos , Modelos Animales de Enfermedad , Fibrosis , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/genética , Inflamación/tratamiento farmacológico , Inflamación/genética , Bleomicina/toxicidad , Bleomicina/uso terapéuticoRESUMEN
Introduction: Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by diffuse fibrosis of the skin and internal organs and vascular abnormalities. The etiology and physiopathology are complex due to the heterogeneity of its overall clinical presentation. Arsenic trioxide (ATO) has been proven to be effective against SSc, sclerodermatous Graft-versus-Host Disease, multiple sclerosis, Crohn's disease or systemic lupus erythematosus animal models and has demonstrated promising effects in human clinical trials. Its efficacy was shown to be related at least in part to the generation of Reactive Oxygen Species (ROS) and the selective deletion of activated immune cells and fibroblasts. However, ATO can induce some adverse effects that must be considered, especially when used for the treatment of a chronic disease. Methods: We evaluate here, in vitro and in a mouse model of SSc, the improved efficacy of ATO when associated with a Fenton-like divalent cation, namely copper chloride (CuCl2), also known to trigger the production of ROS. Results: In preliminary experiments in vitro, ATO 1 µM + CuCl2 0.5 µM increased ROS production and increased apoptosis of NIH 3T3 murine fibroblasts compared to 1 µM ATO alone. In vivo, in the HOCl-induced mouse model of SSc, co-treatment with ATO 2.5 µg/g + CuCl2 0.5 µg/g significantly alleviated clinical signs such as the thickening of the skin (p<0.01) and cutaneous fibrosis, in a manner equivalent to treatment with ATO 5 µg/g. Our results provide evidence that co-treatment with ATO 2.5 µg/g + CuCl2 0.5 µg/g decreases the number of B cells and the activation of CD4+ T lymphocytes. The co-treatment substantially blocks the NRF2 signaling pathway, increases H2O2 production and results in the improvement of the health status of mice with experimental SSc. Conclusion: In conclusion, copper combined with ATO treatment halved the concentration of ATO needed to obtain the same effect as a high dose of ATO alone for the treatment of SSc mice. The strategy of using lower doses of drugs with different mechanisms of action in combination has many potential advantages, the first being to lessen the potential side effects induced by ATO, a drug with side effects quickly increased with dosage.
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Cobre , Esclerodermia Sistémica , Humanos , Animales , Ratones , Trióxido de Arsénico , Especies Reactivas de Oxígeno/metabolismo , Autoinmunidad , Peróxido de Hidrógeno/metabolismo , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/metabolismo , FibrosisRESUMEN
Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation: (a) BWF1 lupus nephritis mice, (b) anti-GBM nephritis, (c) bleomycin-induced systemic sclerosis like skin disease, and (d) bleomycin-induced lung disease. In agreement with the previous studies, BTK inhibitor (BTKB66) treatment was effective in treating lupus nephritis in terms of reducing renal damage both functionally and histologically, accompanied by significant decrease in proteinuria. Both low-dose and high-dose BTKB66 profoundly blocked renal disease in the anti-GBM nephritis model, with efficacy that was comparable to that seen with dexamethasone. This study provides the first evidence that BTK inhibition has both therapeutic and preventative effects in bleomycin-induced SSc-like disease, in terms of reducing skin thickness, fibrosis, collagen deposition, and inflammation. Likewise, significantly lower lung inflammatory cell infiltration was observed after treatment with BTKB66. Therapeutic benefit was associated with lower numbers of macrophages, proliferating macrophages and activated T-cells in the respective injured organs. The observation that these immune cells play key roles in driving end organ inflammation in multiple systemic rheumatic diseases have broad implications for the use of BTKB66 in managing patients with systemic rheumatic diseases where multiple end organs are afflicted, including lupus and systemic sclerosis.
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Nefritis Lúpica , Enfermedades Reumáticas , Esclerodermia Sistémica , Agammaglobulinemia Tirosina Quinasa , Animales , Bleomicina , Modelos Animales de Enfermedad , Inflamación , Nefritis Lúpica/inducido químicamente , Nefritis Lúpica/tratamiento farmacológico , Ratones , Enfermedades Reumáticas/tratamiento farmacológico , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológicoRESUMEN
As part of the reappraisal of the legacy of Wismut AG, 12 patients with silica-induced scleroderma among underground uranium ore mine workers (Wismut AG) under long-term exposure to silica fine dust, as well as radon and its daughter products, during the 1960s and 1970s are reported on. Silica-induced scleroderma is clinically, serologically and immunologically indistinguishable from idiopathic systemic sclerosis. In experimental studies, endothelial cells, monocytes and fibroblasts, as well as their synthesis rates and the release of cytokines and chemokines, were activated by silica fine dust in a way that is consistent with the pathophysiological processes in idiopathic systemic sclerosis. It was not possible to achieve recognition of silica-induced systemic sclerosis as an occupational disease in Germany.
Asunto(s)
Neoplasias Pulmonares , Mineros , Enfermedades Profesionales , Exposición Profesional , Esclerodermia Sistémica , Uranio , Células Endoteliales , Alemania , Humanos , Minería , Enfermedades Profesionales/inducido químicamente , Enfermedades Profesionales/diagnóstico , Enfermedades Profesionales/epidemiología , Exposición Profesional/efectos adversos , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/diagnóstico , Dióxido de Silicio/efectos adversos , Plata , Uranio/efectos adversosRESUMEN
Targeting neuroendocrine receptors can be considered as another interesting approach to treating fibrotic disorders. Previously, we could demonstrate that tropisetron, a classical serotonin receptor blocker, can modulate collagen synthesis and acts in vitro through the α7 nicotinic acetylcholine receptor (α7nAchR). Here, we used a pharmacologic approach with specific α7nAchR agonists to validate this hypothesis. PHA-543613, an α7nAchR-specific agonist, not only prevented but also reversed established skin fibrosis of mice injected with bleomycin. Interestingly, agonistic stimulation of α7nAchR also attenuated experimental skin fibrosis in the non-inflammation driven adenovirus coding for TGFß receptor Iact mouse model, indicating fibroblast-mediated and not only anti-inflammatory effects of such agents. The fibroblast-mediated effects were confirmed in vitro using human dermal fibroblasts, in which the α7nAchR-specific agonists strongly reduced the impact of TGFß1-mediated expression on collagen and myofibroblast marker expression. These actions were linked to modulation of the redox-sensitive transcription factor JunB and impairment of the mitochondrial respiratory system. Our results indicate that pharmacologic stimulation of the α7nAchR could be a promising target for treatment of patients with skin fibrotic diseases. Moreover, our results suggest a mechanistic axis of collagen synthesis regulation through the mitochondrial respiratory system.
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Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Quinuclidinas/farmacología , Esclerodermia Sistémica/tratamiento farmacológico , Piel/patología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Adenoviridae/genética , Animales , Bleomicina/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Células Cultivadas , Colágeno/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Masculino , Ratones , Cultivo Primario de Células , Quinuclidinas/uso terapéutico , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Piel/citología , Piel/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
BACKGROUND: Increasing evidence indicated that the cannabinoid receptors were involved in the pathogenesis of organ fibrogenesis. PURPOSE: The purpose of this study was to discover novel cannabinoid receptor 2 (CB2) agonist and assess the potential of CB2 activation in treating systemic sclerosis. METHODS: A gaussia princeps luciferase-based split luciferase complementation assay (SLCA) was developed for detection of the interaction between CB2 and ß-arrestin2. A library of 366 natural products was then screened as potential CB2 agonist using SLCA approach. Several GPCR functional assays, including HTRF-based cAMP assay and calcium mobilization were also utilized to evaluated CB2 activation. Bleomycin-induced experimental systemic sclerosis was used to assess the in vivo anti-fibrotic effects. Dermal thickness and collagen content were evaluated via H&E and sirius red staining. RESULTS: Celastrol was identified as a new agonist of CB2 by using SLCA. Furthermore, celastrol triggers several CB2-mediated downstream signaling pathways, including calcium mobilization, inhibition of cAMP accumulation, and receptor desensitization in a dose-dependent manner, and it has a moderate selectivity on CB1. In addition, celastrol exhibited the anti-inflammatory properties on lipopolysaccharide (LPS) treated murine Raw 264.7 macrophages and primary macrophages. Finally, we found that celastrol exerts anti-fibrotic effects in the bleomycin-induced systemic sclerosis mouse model accompanied by reduced inflammatory conditions. CONCLUSION: Taken together, celastrol is identified a novel selective CB2 agonist using a new developed arrestin-based SLCA, and CB2 activation by celastrol reduces the inflammatory response, and prevents the development of dermal fibrosis in bleomycin-induced systemic sclerosis mouse model.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Receptor Cannabinoide CB2/agonistas , Esclerodermia Sistémica/tratamiento farmacológico , Triterpenos/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Arrestina/metabolismo , Bleomicina/toxicidad , Calcio/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Fibrosis , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Triterpenos Pentacíclicos , Células RAW 264.7 , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Triterpenos/químicaRESUMEN
BACKGROUND: Recent studies have demonstrated that systemic or topical PUVA therapy, i.e., ultraviolet A (UVA) irradiation following treatment with 8-methoxypsoralen (8-MOP), is effective against the sclerotic skin lesions in systemic sclerosis. However, the mechanisms still remain unknown. OBJECTIVE: To clarify the mechanisms of this therapy, we created a mouse model of bleomycin (BLM) injection-induced scleroderma and evaluated the effects of PUVA on the fibrotic lesions of scleroderma in this mouse model. METHODS: BLM was injected subcutaneously once a day into the mice for 24 days. During the injection period, one group of mice was irradiated with UVA following local application of 8-MOP. Control groups were also set up, which were injected with phosphate-buffered saline, instead of BLM. Skin tissue samples examined histopathologically changes, measured of the content of hydroxyproline, and checked for the expression of genes encoding type I collagen, type III collagen, and transforming growth factor-ß1 (TGF-ß1). RESULTS: The mouse models of scleroderma was found to show an increase in the density of the collagen fibers and thickening of the dermis and increased expressions of type I collagen, type III collagen, and TGF-ß1. However, the combination of BLM treatment and topical PUVA treatment mice appeared reduced the dermal thickness and hydroxyproline content, down-regulation of expressions of the type I and type III collagen genes was observed while the expression of the TGF-ß1 gene remained unchanged. CONCLUSION: These results suggest that the effectiveness of topical PUVA therapy is attributable to the down-regulation of the expressions of the collagen genes by this treatment. The results additionally suggest that is not mediated by down-regulated expression of the TGF-ß1.
Asunto(s)
Colágeno Tipo III/metabolismo , Colágeno Tipo I/metabolismo , Metoxaleno/administración & dosificación , Terapia PUVA , Fármacos Fotosensibilizantes/administración & dosificación , Esclerodermia Sistémica/tratamiento farmacológico , Piel/efectos de los fármacos , Administración Cutánea , Animales , Bleomicina , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Hidroxiprolina/metabolismo , Ratones , Ratones Endogámicos C3H , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/metabolismo , Piel/patología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Silicone, a synthetic polymer considered to be a biologically inert substance, is used in a multitude of medical products, the most publicly recognized of which are breast implants. Silicone breast implants have been in use since the early 1960s for cosmetic and reconstructive purposes, and reports of autoimmune disease-like syndromes began appearing in the medical literature soon thereafter. Over the previous year, silicone implants have been suggested as playing a role in a new syndrome that encompasses a wide array of immune-related manifestations, termed ASIA ('Autoimmune Syndrome Induced by Adjuvant'). Scleroderma, a relatively rare connective tissue disease with skin manifestations and systemic effects, has also been described in association with silicone implantation and rupture. However, epidemiological studies and meta-analyses have failed to corroborate the clinical impression of silicone-induced scleroderma. The following review describes the mechanisms by which silicone may mediate autoimmunity in general, as well as the evidence for causal associations with more specific autoimmune syndromes in general, and scleroderma in particular.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Implantes de Mama/efectos adversos , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/inmunología , Siliconas/efectos adversos , Autoinmunidad/inmunología , Ensayos Clínicos como Asunto , Ambiente , Humanos , Factores de RiesgoRESUMEN
OBJECTIVES: There is increasing evidence that the endocannabinoid system may be involved in pathological fibrosis, and that its modulation might limit fibrotic responses. The aim of this study was to examine the capacity of a synthetic cannabinoid receptor agonist to modify skin fibrosis in the bleomycin mouse model of scleroderma. METHODS: Skin fibrosis was induced by local injections of bleomycin in two groups of DBA/2J mice. One group was cotreated with the synthetic cannabinoid WIN55,212-2 at 1 mg/kg/day. Skin fibrosis was evaluated by histology and skin thickness and hydroxyproline content were quantified. Markers of fibroblast activation, including α smooth muscle actin and the profibrotic cytokines transforming growth factor (TGF)ß, connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF)-BB, were examined. Levels of PSMAD2/3, which are crucial in extracellular matrix overproduction, were analysed. RESULTS: Bleomycin treatment induced typical skin fibrosis. Upon WIN55,212-2 treatment dermal fibrosis was completely prevented. Subcutaneous inflammatory cell infiltration, dermal thickness and collagen content resulted similar to those of the control group. The synthetic cannabinoid prevented fibroblasts activation induced by bleomycin, paralleled by a strong inhibition of TGFß, CTGF and PDGF-BB expression. Phosphorylation of SMAD2/3 was significantly downregulated after WIN55,212-2 exposure. CONCLUSIONS: Taken together, the results indicate that the synthetic cannabinoid WIN55,212-2 is capable of preventing skin fibrosis in a mouse model of scleroderma.
Asunto(s)
Benzoxazinas/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Piel/patología , Animales , Bleomicina , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Fibroblastos/efectos de los fármacos , Fibrosis , Ratones , Ratones Endogámicos DBA , Factor de Crecimiento Derivado de Plaquetas/fisiología , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/complicaciones , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/fisiologíaAsunto(s)
Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , Adulto , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Colectomía , Neoplasias del Colon/cirugía , Femenino , Humanos , Nifedipino/uso terapéutico , Esclerodermia Sistémica/patología , Resultado del TratamientoRESUMEN
Nephrogenic systemic fibrosis (NSF) is a recently described, highly debilitating scleroderma-like disease occurring in patients with severe or end-stage renal failure. NSF is characterized by cutaneous papules and coalescing plaques ("peau d'orange" appearance) and a wooden consistency. It may ultimately cause disabling contractures of several joints, thus making many patients wheelchair-dependent. NSF has been associated to prior administration of gadolinium chelates (GC) used as contrast agents for magnetic resonance imaging. The best available treatment option at the present time is renal transplantation. The mechanism of NSF has not been fully elucidated. Several hypotheses have been proposed so far and are critically discussed in the present review article. Gadolinium has been found in skin biopsy samples of patients. The most widely accepted hypothesis is related to dechelation of less stable GC, progressively releasing free Gd3+ which may subsequently lead to the attraction of CD34+, CD45+, pro-collagen+ circulating fibrocytes via the release of chemokines, thereby inducing systemic fibrosing disorders. Pre-existing renal failure may facilitate the process by delaying the excretion of GC. A complex interplay between gadolinium and co-factors (pro-inflammatory status, vascular injury, high dose of erythropoietin, high levels of calcium, phosphorus, etc.) may occur in patients with impaired renal function. This and other hypotheses remain to be investigated, as well as the role and independence of co-factors.
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Quelantes/efectos adversos , Medios de Contraste/efectos adversos , Gadolinio/efectos adversos , Fallo Renal Crónico/inducido químicamente , Esclerodermia Sistémica/inducido químicamente , Humanos , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: To study the effects of Wenyang Chubi Decoction (WYCBD), a compound traditional Chinese herbal medicine, on connective tissue growth factor (CTGF) and collagen-I (COL-I) in a mouse model of scleroderma. METHODS: Scleroderma was induced in BALB/c mice by daily local injection of bleomycin for three weeks and the mice were randomly divided into untreated, WYCBD-treated and normal saline (NS) treated groups, with another group of BALB/c mice as normal control. WYCBD and NS were given orally for one month respectively. Histopathology in the skin and lungs of the mice were examined. The CTGF and COL-I expressions in the skin or skin lesions were detected by immunohistochemical Elivision assay. RESULTS: The expression levels of CTGF and COL-I in the untreated group were significantly higher than those in the normal control group (P<0.05). Compared with the NS-treated group, the WYCBD-treated group had significant improvement in the skin and lung histopathology and remarkably decreased expression levels of CTGF and COL-I (P<0.05). CONCLUSION: Scleroderma mice showed high expressions of CTGF and COL-I in the skin. WYCBD had the effects of decreasing the CTGF and COL-I expressions and improving the skin fibrosis.
Asunto(s)
Colágeno Tipo I/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Esclerodermia Sistémica/tratamiento farmacológico , Animales , Bleomicina , Femenino , Ratones , Ratones Endogámicos BALB C , Distribución Aleatoria , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/metabolismo , Piel/metabolismoRESUMEN
Although the association between administration of the antitumor agent bleomycin and the development of cutaneous fibrosis is established, there are only a small number of cases of bleomycin-induced scleroderma described in the literature. We report the development of generalised scleroderma with wide spread hyperpigmentation in a 52-year-old male patient, who received a total dose of 360 mg bleomycin in combination with cisplatin and etoposid for therapy of a malignant testicular seminoma. The clinical cutaneous alterations as well as the histological findings were indistinguishable from those encountered in progressive systemic sclerosis (PSS). In contrast to PSS however, Raynaud's phenomenon, cutaneous calcinosis, teleangiectasia, arthritis and involvement of additional organs were all absent. PSS-typical auto-antibodies were negative. Even 18 months after discontinuation of the drug and treatment with UVA1 phototherapy (3-4 times per week with 20 J/cm2) as well as physiotherapy, the skin changes had still not resolved. Based on our case and a detailed review of the literature, we discuss characteristics of bleomycin-induced scleroderma including pathogenesis, treatment modalities and course.
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Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/efectos adversos , Esclerodermia Sistémica/inducido químicamente , Seminoma/tratamiento farmacológico , Neoplasias Testiculares/tratamiento farmacológico , Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/patología , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
Several reports have implicated an association between the development of connective tissue disorders and exposure to silicone in breast implant patients. These connective tissue disorders include local or systemic scleroderma-like syndrome and have been characterized by fibrosis as well as the presence of circulating autoantibodies. Whether silicone does potentiate the development of a scleroderma-like syndrome is still to be defined. The purpose of the present study was to determine the effect of silicone on the tight skin (TSK/+) mouse which develops a scleroderma-like syndrome and on its normal pa/pa TSK/- littermate. Groups of six TSK and five of their normal pa/pa littermates were injected subcutaneously with low molecular weight silicone (LMW-PDMS), high molecular weight silicone gel (HMW-PDMS), incomplete Freunds' adjuvant (IFA) or Hank's balanced salt solution (HBSS) in the dorsal neck area and ventrally in the upper chest region. Serum was obtained prior to and 1 month after injection of silicone, IFA, or control HBSS. Antibody levels to bovine serum albumin (BSA), RNA polymerase (RNAP) and topoisomerase I were determined. Mice were then euthanized and strips of skin from the injection sites as well as samples of kidney and liver were studied histologically. No significant pathological changes were observed in TSK/- mice 1 month following injection with HBSS, LMW-PDMS or HMW-PDMS. Skin samples from TSK/+ mice which received LMW-PDMS showed hyperplasia of the dermis and peri-panniculus carnosus tissue and infiltrates of macrophages containing lipid-like vacuolated materials. Lipid vacuoles were observed throughout the deeper dermis as multiple loculated vacuoles. TSK mice which received HMW-PDMS showed similar thickening of the dermis and the peri-panniculus carnosus connective tissue. There were no significant differences in the histologic characteristics of the silicone-injected TSK/+ mice compared to those that received HBSS or IFA. No detectable changes in the kidney, spleen, or liver samples taken from TSK/+ or TSK/- mice injected with HBSS, IFA or silicone (LMW-PDMS, HMW-PDMS) preparations were noted. Baseline circulating antibody levels to BSA, RNAP and topoisomerase were significantly higher in TSK/+ mice compared to the control TSK/- littermates. Administration of silicone (LMW-PDMS or HMW-PDMS) did not significantly alter circulating antibody levels to BSA, RNAP and topoisomerase in either the TSK/+ or the TSK/- mice. The results of this study indicate that silicone administration does not potentiate the development of the scleroderma-syndrome characterized by skin lesions and presence of circulating antibodies in the TSK/+ model.
Asunto(s)
Ratones Mutantes/inmunología , Esclerodermia Sistémica/inducido químicamente , Siliconas/farmacología , Animales , Autoanticuerpos/sangre , Modelos Animales de Enfermedad , Sinergismo Farmacológico , RatonesRESUMEN
Systemic sclerosis (scleroderma) is a connective tissue disease with a wide range of clinical manifestations, with high or low degrees of skin and internal organ involvement together with different antinuclear antibody (ANA) specificities. Several studies provide evidence that males, who are rarely affected by systemic sclerosis, have an increased risk when working in mines. Therefore we reinvestigated 21 male subjects and 6 cases of deceased male patients who had been engaged in East German uranium mines and had shown evidence of this disease in medical examinations. Dermatological investigations, evaluation of chest X-rays and autoantibody estimation were performed. PCR-sequence-specific oligonucleotide typing was used to study the genetic association of HLA-D alleles with autoantibodies typical for scleroderma in these uranium miners suffering from systemic sclerosis and in patients with idiopathic systemic sclerosis. The determined HLA phenotype frequencies and the following statistical analysis (Fisher's exact test (2-sided)) revealed that in comparison with randomly selected controls, alleles DRB1*0300 (DR3) and DQB1*0201 (DQ2) were distinctly increased in the group of affected uranium miners, especially in those with anti-Scl-70 positivity. In contrast, we did not observe significant differences between affected and unaffected miners. Comparing anti-Scl-70-positive affected uranium miners with anti-Scl-70-positive idiopathic systemic sclerosis cases. DRB1*0300 as well as DQB1*0201 were also significantly enhanced in the former group. ACA-positive systemic sclerosis miners had significantly elevated frequencies in DRB1*0100 (DR1) and DRB1*0800 (DR8) only in comparison with unaffected miners and unexposed controls. Our genetic and immunological data lead to the assumption that a different set of HLA-D alleles in combination with exogenous factors is involved in the induction of anti-Scl-70 antibodies in uranium miners that might influence their susceptibility to the disease, whereas the same occupational exposure seems to have no influence on the induction of ACA antibodies.
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Enfermedades Profesionales/inducido químicamente , Esclerodermia Sistémica/inducido químicamente , Uranio/efectos adversos , Adulto , Anciano , Autoanticuerpos/sangre , Susceptibilidad a Enfermedades , Femenino , Antígenos HLA-D/genética , Humanos , Masculino , Persona de Mediana Edad , Minería , Enfermedades Profesionales/genética , Enfermedades Profesionales/inmunología , Exposición Profesional/efectos adversos , Factores de Riesgo , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/inmunologíaAsunto(s)
Modas Dietéticas , Síndrome de Eosinofilia-Mialgia/inducido químicamente , Esclerodermia Sistémica/inducido químicamente , Triptófano/efectos adversos , Adulto , Brassica , Ácidos Grasos Monoinsaturados , Femenino , Humanos , Persona de Mediana Edad , Aceites de Plantas/envenenamiento , Aceite de Brassica napusRESUMEN
Scleroderma-like diseases can be induced by a number of chemical compounds, such as plastics, solvents and drugs. Contaminated rapeseed oil was the cause of the toxic oil syndrome and L-tryptophan induces the so-called eosinophilia-myalgia-syndrome. On the other hand, paraffin and silicon can trigger so-called adjuvant disease, while long-term exposure to silica can lead to idiopathic scleroderma (associated with silicosis in some cases). In addition to the clinical features, some pathogenetic data in the literature, such as genetic factors (HLA, chromosomal anomalies, enzyme deficiencies) and the metabolism of chlorinated ethylenes via reactive epoxide intermediate products, and our own findings are reported. Silica-induced scleroderma cannot be distinguished from the idiopathic form by epidemiological, clinical or immunological studies or by parameters referring to the blood vessels or collagen metabolism. In cell culture studies it has been shown that macrophages/monocytes release IL1, IL6 and TNF after ingestion of silica, which affects fibroblasts, T-helper cells and endothelial cells. Comparative results from the silicosis literature are reported. Finally, the possibly stimulating role of ionizing irradiation (uranium mining) in favouring the development of scleroderma is discussed.
Asunto(s)
Esclerodermia Sistémica/inducido químicamente , Etilenos/efectos adversos , Humanos , Cuarzo/efectos adversos , Factores de Riesgo , Esclerodermia Sistémica/genética , Siliconas/efectos adversosRESUMEN
In 1981 epidemic poisoning with adulterated cooking oil occurred in Spain, affecting more than 20,000 people. The condition caused has since become known as the toxic oil syndrome (TOS). About 10-15% of the patients with acute symptoms developed a chronic disease with scleroderma-like skin manifestations, polyneuropathy and myositis. While the acute phase of the TOS was characterized by eosinophilia and elevated IgE, the chronic stage involved humoral autoimmune phenomena, such as antinuclear and antinucleolar antibodies, in many cases. In women with the chronic phase of TOS there was a possible prevalence of HLA-DR3 and HLA-DR4. The recently characterized eosinophilia-myalgia syndrome (EMS), which is thought to have been induced by contaminated L-tryptophan preparations, is similar to the TOS in some particulars. Understanding of the toxicological, immunological and genetic pathways leading to these diseases might give us some insight into the pathogenesis of spontaneously occurring autoimmune diseases, such as systemic scleroderma.
Asunto(s)
Anticuerpos Antinucleares/análisis , Enfermedades Autoinmunes/inducido químicamente , Brassica , Síndrome de Eosinofilia-Mialgia/inducido químicamente , Contaminación de Alimentos , Enfermedades Transmitidas por los Alimentos/inmunología , Aceites de Plantas/envenenamiento , Esclerodermia Sistémica/inducido químicamente , Animales , Enfermedades Autoinmunes/inmunología , Síndrome de Eosinofilia-Mialgia/inmunología , Ácidos Grasos Monoinsaturados , Antígenos HLA/análisis , Humanos , Aceite de Brassica napus , Esclerodermia Sistémica/inmunología , EspañaRESUMEN
Interaction of the host immune system with certain substances found in the environment will, in the presence of other unknown factors such as genetic susceptibility, lead to aberrant immune responses manifested as disease. In most of the conditions discussed above, simple removal from exposure to the offending agent does not lead to resolution. This suggests that an ongoing response has been triggered which cannot immediately be turned off, perhaps due to continued presence of the substance such as in human adjuvant disease where paraffin or silicone has been found in lymphoid tissue. Scleroderma remains a disease of uncertain cause for which our present treatment is inadequate. Illnesses presented in this chapter resemble the natural form of the disease in many ways and may provide useful insight into its pathogenesis. In the short term, recognition of exposure to environmental hazards which appear to pose risk will prevent additional cases of disabling illness. Study of chemically induced forms of scleroderma may, in the future, allow us to predict potential toxicity of chemically similar compounds. If we could learn how they trigger disease, researchers might be able to apply the information to understanding the pathogenesis of naturally-occurring scleroderma.
Asunto(s)
Enfermedades Profesionales/inducido químicamente , Esclerodermia Sistémica/inducido químicamente , Exposición a Riesgos Ambientales , HumanosRESUMEN
For the stimulation of research on scleroderma and the prophylaxis of occupational scleroderma-like diseases and the prevention of iatrogenic injuries, respect., it is important to know the inducing environmental substances. Plastics (vinyl chloride, epoxy resins), solvents (chlorinated, aromatic and aliphatic hydrocarbons), drugs (bleomycin, pentazocine), cocaine (abuse) and contaminated rapeseed oil are more or less able to induce scleroderma-like diseases. Vinyl chloride disease is the best known among these. The toxic oil syndrome represents the most inglorious example of the recent time. Paraffin and silicon can act as adjuvants and induce a progressive systemic sclerosis. In our studies it could be shown, that silica is able to induce not only a silicosis, but also a true progressive systemic sclerosis after long term exposure. Acknowledgment of such cases as an occupational disease is justified and regulated by law in the German Democratic Republic.