RESUMEN
Systemic sclerosis is a disease characterized by skin and internal organ fibrosis, lacking specific therapeutic drugs and having a poor prognosis. Early diagnosis and intervention of the disease is of significant value in improving patient prognosis. This article provides a systematic review of the early diagnosis and treatment of systemic sclerosis, including early symptom recognition, laboratory testing, and drug intervention. It will provide a reference for the prevention of this disease.
Asunto(s)
Esclerodermia Sistémica , Humanos , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/prevención & controlRESUMEN
Systemic sclerosis is a disease characterized by skin and internal organ fibrosis, lacking specific therapeutic drugs and having a poor prognosis. Early diagnosis and intervention of the disease is of significant value in improving patient prognosis. This article provides a systematic review of the early diagnosis and treatment of systemic sclerosis, including early symptom recognition, laboratory testing, and drug intervention. It will provide a reference for the prevention of this disease.
Asunto(s)
Humanos , Esclerodermia Sistémica/prevención & controlRESUMEN
Systemic sclerosis is a disease characterized by skin and internal organ fibrosis, lacking specific therapeutic drugs and having a poor prognosis. Early diagnosis and intervention of the disease is of significant value in improving patient prognosis. This article provides a systematic review of the early diagnosis and treatment of systemic sclerosis, including early symptom recognition, laboratory testing, and drug intervention. It will provide a reference for the prevention of this disease.
Asunto(s)
Humanos , Esclerodermia Sistémica/prevención & controlRESUMEN
BACKGROUND: Systemic sclerosis (SSc) causes progressive fibrosis of multiple organs with the low efficacy of immunosuppressive therapies. Our previous study indicated the SSc pathological pathways are closely correlated with Ca2+ signals, and blockage of the intracellular Ca2+ elevation facilitates inhibition of SSc pathogenesis. OBJECTIVE: Transforming growth factor ß (TGF-ß)-modulated SMAD signaling is crucial in regulating SSc pathogenesis. Whether Ca2+ signals are involved in TGF-ß1/SMAD signaling-induced fibrotic process has been further investigated. METHODS: We utilized TGF-ß1-induced myofibroblasts as a model to detect how Ca2+ signals affected SSc pathogenesis, and investigated the combination of treatment with store-operated Ca2+ entry (SOCE) associated inhibitors, 2-aminoethyl diphenylborinate (2-APB) and SKF96365 to restrain the increased Ca2+ signaling in myofibroblasts. In addition, the SSc bleomycin mouse model was used to detect the effect of 2-APB on SSc pathogenesis in vivo. RESULTS: Our findings revealed increased levels of TGF-ß1 production in SSc was associated with intracellular Ca2+ activity, and inhibition of intracellular Ca2+ regulation by 2-APB resulted in the dedifferentiation of TGF-ß1-induced myofibroblasts. This was due to the fact that 2-APB restrained the expression fibrotic markers, α-SMA, fibronectin and vimentin through inhibiting TGF-ß1/SMAD3 signaling. Thus, subcutaneous injection of 2-APB improved bleomycin-induced skin and pulmonary fibrosis. CONCLUSION: 2-APB is a potential candidate for treating fibrosis, by disrupting intracellular Ca2+ regulation in SSc to induce the dedifferentiation of myofibroblasts and meliorates fibrosis pathogenesis via inhibiting TGF-ß1/SMAD3 signaling.
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Compuestos de Boro/uso terapéutico , Señalización del Calcio/efectos de los fármacos , Desdiferenciación Celular/efectos de los fármacos , Fibrosis Pulmonar/prevención & control , Esclerodermia Sistémica/prevención & control , Adulto , Anciano , Animales , Bleomicina , Compuestos de Boro/farmacología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Fibrosis Pulmonar/metabolismo , Esclerodermia Sistémica/metabolismo , Adulto JovenRESUMEN
Although the pathogenesis of systemic sclerosis is not exactly known, it is thought that immune activation has prominent roles in pathogenesis. Secukinumab is a monoclonal antibody against interleukin (IL)-17A. Metformin, a widely used antidiabetic medication, has anti-proliferative, immunomodulating and anti-fibrotic activities. The purpose of our study is to determine the therapeutic efficacy of secukinumab and metformin on bleomycin (BLM) induced dermal fibrosis. Fifty Balb/c female mice were divided into 5 groups: (group 1 control, 2 sham, 3 secukinumab, 4 metformin and 5 secukinumab + metformin). The mice in the control group received 100 µL phosphate-buffered saline (PBS), while the mice in other groups received 100 µL (100 µg) BLM in PBS subcutaneously (sc) every day for 4 weeks. In addition, mice in groups 3 and 5 received secukinumab at a dose of 10 mg/kg/wk sc, and mice in the groups 4 and 5 received oral metformin 50 mg/kg/d for 28 days. All groups of mice were sacrificed at the end of the 4th week and tissue samples were taken for analysis. In addition to histopathological analysis, skin tissue messenger RNA (mRNA) expressions of IL-17 and collagen 3A were measured by real-time polymerase chain reaction. Repeated BLM injections had caused dermal fibrosis. In addition, the mRNA expressions of IL-17 and collagen 3A were increased in the BLM group. Secukinumab and metformin ameliorated dermal fibrosis. They decreased dermal thickness and tissue IL-17A and collagen 3A mRNA levels. Secukinumab and metformin exhibit anti-fibrotic effects in the BLM-induced dermal fibrosis.
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Anticuerpos Monoclonales Humanizados/farmacología , Bleomicina/farmacología , Fibrosis/inducido químicamente , Metformina/farmacología , Esclerodermia Sistémica/inducido químicamente , Enfermedades de la Piel/inducido químicamente , Animales , Bleomicina/efectos adversos , Bleomicina/toxicidad , Colágeno/metabolismo , Modelos Animales de Enfermedad , Femenino , Inyecciones Subcutáneas , Interleucina-17/metabolismo , Ratones , Ratones Endogámicos BALB C , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/prevención & control , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Piel/metabolismo , Enfermedades de la Piel/metabolismoRESUMEN
Scleroderma is an autoimmune disease caused by the abnormal regulation of extracellular matrix synthesis and is activated by non-regulated inflammatory cells and cytokines. Echinochrome A (EchA), a natural pigment isolated from sea urchins, has been demonstrated to have antioxidant activities and beneficial effects in various disease models. The present study demonstrates for the first time that EchA treatment alleviates bleomycin-induced scleroderma by normalizing dermal thickness and suppressing collagen deposition in vivo. EchA treatment reduces the number of activated myofibroblasts expressing α-SMA, vimentin, and phosphorylated Smad3 in bleomycin-induced scleroderma. In addition, it decreased the number of macrophages, including M1 and M2 types in the affected skin, suggesting the induction of an anti-inflammatory effect. Furthermore, EchA treatment markedly attenuated serum levels of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, in a murine scleroderma model. Taken together, these results suggest that EchA is highly useful for the treatment of scleroderma, exerting anti-fibrosis and anti-inflammatory effects.
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Antiinflamatorios/farmacología , Macrófagos/efectos de los fármacos , Miofibroblastos/efectos de los fármacos , Naftoquinonas/farmacología , Esclerodermia Sistémica/prevención & control , Piel/efectos de los fármacos , Actinas/metabolismo , Animales , Bleomicina , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Humanos , Mediadores de Inflamación/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/inmunología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Fosforilación , Células RAW 264.7 , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/metabolismo , Piel/inmunología , Piel/metabolismo , Piel/patología , Proteína smad3/metabolismo , Vimentina/metabolismoRESUMEN
Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor ß-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) â BALB/c (H-2d) and LP/J (H-2b) â C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Piranos/farmacología , Compuestos de Pirvinio/farmacología , Esclerodermia Sistémica/prevención & control , Sulfonas/farmacología , Triazoles/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antibacterianos/farmacología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patologíaRESUMEN
BACKGROUND: Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models. METHODS: The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-ß signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated. RESULTS: DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor ß1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1ß, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-ß1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-ß/Smad signaling pathway. CONCLUSIONS: DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.
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Adenina/análogos & derivados , Butiratos/farmacología , Dermis/efectos de los fármacos , Inflamación/prevención & control , Esclerodermia Sistémica/prevención & control , Enfermedades Vasculares/prevención & control , Adenina/farmacología , Animales , Bleomicina , Línea Celular , Células Cultivadas , Dermis/metabolismo , Dermis/patología , Modelos Animales de Enfermedad , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis/inducido químicamente , Fibrosis/prevención & control , Expresión Génica/efectos de los fármacos , Humanos , Inflamación/genética , Inflamación/metabolismo , Macrófagos/clasificación , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/metabolismo , Células THP-1 , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Enfermedades Vasculares/genética , Enfermedades Vasculares/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-α-induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-κB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-ß/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.
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Fibrosis Pulmonar , Esclerodermia Sistémica , Sirtuina 1/metabolismo , Animales , Línea Celular , Activación Enzimática , Femenino , Humanos , Masculino , Ratones , FN-kappa B/metabolismo , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/prevención & control , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/enzimología , Esclerodermia Sistémica/prevención & control , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. Although the involvement of connective tissue growth factor (CTGF/CCN2) has been well-documented in SSc fibrosis, the therapeutic potential of targeting CTGF in SSc has not been fully investigated. Our aim was to examine the therapeutic potential of CTGF blockade in a preclinical model of SSc using two approaches: smooth muscle cell fibroblast-specific deletion of CTGF (CTGF knockout (KO)) or a human anti-CTGF monoclonal antibody, FG-3019. METHODS: Angiotensin II (Ang II) was administered for 14 days by subcutaneous osmotic pump to CTGF KO or C57BL/6 J mice. FG-3019 was administered intraperitoneally three times per week for 2 weeks. Skin fibrosis was evaluated by histology and hydroxyproline assay. Immunohistochemistry staining was used for alpha smooth muscle actin (αSMA), platelet-derived growth factor receptor ß (PDGFRß), pSmad2, CD45, von Willebrand factor (vWF), and immunofluorescence staining was utilized for procollagen and Fsp1. RESULTS: Ang II-induced skin fibrosis was mitigated in both CTGF KO and FG-3019-treated mice. The blockade of CTGF reduced the number of cells expressing PDGFRß, procollagen, αSMA, pSmad2, CD45, and Fsp1 in the dermis. In addition, inhibition of CTGF attenuated vascular injury as measured by the presence of vWF-positive cells. CONCLUSIONS: Our data indicate that inhibition of CTGF signaling presents an attractive therapeutic approach in SSc.
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Anticuerpos Monoclonales/farmacología , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Esclerodermia Sistémica/prevención & control , Piel/efectos de los fármacos , Actinas/metabolismo , Angiotensina II , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Células Cultivadas , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/inmunología , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis/inducido químicamente , Fibrosis/prevención & control , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Esclerodermia Sistémica/inmunología , Piel/metabolismo , Piel/patologíaRESUMEN
OBJECTIVES: Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc. METHODS: The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-ß-receptor I. RESULTS: Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis. CONCLUSIONS: These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.
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Aminopiridinas/uso terapéutico , Proteínas de la Membrana/antagonistas & inhibidores , Piperazinas/uso terapéutico , Esclerodermia Localizada/prevención & control , Esclerodermia Sistémica/prevención & control , Piel/patología , Vía de Señalización Wnt/efectos de los fármacos , Aciltransferasas , Aminopiridinas/farmacología , Animales , Bleomicina , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Fibrosis , Enfermedad Injerto contra Huésped/complicaciones , Ratones Endogámicos BALB C , Piperazinas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/prevención & control , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Esclerodermia Localizada/etiología , Esclerodermia Localizada/metabolismo , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: The capillary networks are less dense and have irregular structures in scleroderma. These abnormalities result in lower capillary blood flow causing severe tissue hypoxia, which is a major stimulus for angiogenesis. However, current knowledge about compensatory angiogenesis is ambiguous in scleroderma. Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF). OBJECTIVES: The aim of the present study is to evaluate the protective effects of bevacizumab in bleomycin (BLM)- -induced dermal fibrosis. MATERIAL AND METHODS: This study involved 4 groups of Balb/c mice (n = 10 per group). Mice in the control group received 100 µL/day of phosphate-buffered saline (PBS) subcutaneously, while the other 3 groups were given 100 µg/day of BLM (dissolved in 100 µL PBS) subcutaneously, for 4 weeks. Mice in BLM-treated 3rd and 4th groups also received bevacizumab (1 or 5 mg/kg twice a week, intraperitoneally). At the end of the fourth week, all mice were sacrificed and blood and tissue samples were obtained. RESULTS: The BLM applications increased the dermal thicknesses, tissue hydroxyproline contents, and α-smooth muscle actin-positive (α-SMA+) cell counts, and led to histopathologically prominent dermal fibrosis. The bevacizumab treatments decreased the tissue hydroxyproline contents and dermal thicknesses, and these improvements were more prominent at doses by which α-SMA+ cell counts were markedly decreased, in the BLM-injected mice. CONCLUSIONS: In our study, inhibition of VEGF with bevacizumab treatments prevented the BLM-induced dermal fibrosis suggesting that VEGF expression contributes to the pathogenesis of scleroderma.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Bevacizumab/farmacología , Bleomicina , Esclerodermia Sistémica/prevención & control , Piel/efectos de los fármacos , Actinas/metabolismo , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fibrosis , Hidroxiprolina/metabolismo , Ratones Endogámicos BALB C , Neovascularización Patológica , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/irrigación sanguínea , Piel/metabolismo , Piel/patología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4(+) T cells (CD4(+)Tconvs) but demethylated in Tregs. METHODS: Here, we assessed the impact of azacytidine (AZA) on cGVHD in a well-established murine model of sclerodermic cGVHD (B10.D2 (H-2d) â BALB/cJ (H-2d)). RESULTS: The administration of AZA every 48 h from day +10 to day +30 at the dose of 0.5 mg/kg or 2 mg/kg mitigated chronic GVHD. Further, AZA-treated mice exhibited higher blood and thymic Treg frequencies on day +35, as well as higher demethylation levels of the Foxp3 enhancer and the IL-2 promoter in splenocytes at day +52. Interestingly, Tregs from AZA-treated mice expressed more frequently the activation marker CD103 on day +52. AZA-treated mice had also lower counts of CD4(+)Tconvs and CD8(+) T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4(+)Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells. CONCLUSIONS: Our results indicate that AZA prevented sclerodermic cGVHD in a well-established murine model of cGVHD. These data might serve as the basis for a pilot study of AZA administration for cGVHD prevention in patients at high risk for cGVHD.
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Azacitidina/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Esclerodermia Sistémica/prevención & control , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Trasplante de Médula Ósea/efectos adversos , Proliferación Celular/efectos de los fármacos , Metilación de ADN , Esquema de Medicación , Factores de Transcripción Forkhead/genética , Recuento de Linfocitos , Ratones , Ratones Endogámicos BALB C , Bazo/citología , Linfocitos T Reguladores/inmunologíaAsunto(s)
Organizaciones de Beneficencia/organización & administración , Enfermedad de Raynaud/prevención & control , Esclerodermia Localizada/prevención & control , Esclerodermia Sistémica/prevención & control , Humanos , Objetivos Organizacionales , Enfermedad de Raynaud/epidemiología , Esclerodermia Localizada/epidemiología , Esclerodermia Sistémica/epidemiología , Reino Unido/epidemiologíaRESUMEN
No disponible
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Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/prevención & control , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/epidemiología , Esclerodermia Sistémica/prevención & control , Tejido Conectivo/patología , Grupos de Riesgo , Cateterismo Venoso Central/tendencias , Cateterismo Cardíaco/métodos , Cateterismo Cardíaco/tendenciasRESUMEN
OBJECTIVES: The pathogenesis of fibrosis in scleroderma (SSc) is unknown. TGF-ß and platelet-derived growth factor are important in the development of fibrosis and tyrosine kinases are involved in these pathways. The possible antifibrotic effects of various kinase inhibitors in SSc have been studied before. Spleen tyro-sine kinase (Syk) is a protein tyrosine kinase which activates intracellular signal transduction pathways; and has been claimed to be involved in the pathogenesis of systemic autoimmune diseases. Inhibition of Syk suppresses IgE- and IgG-associated FcR signal activation in various cell types; and suppresses experimental arthritis and skin and kidney disease in lupus-prone mice. We investigated the ability of a small drug, the Syk inhibitor, fostamatinib, to protect mice from bleomycin-induced SSc. METHODS: Four study groups of BALB/c mice were included into this study: control, bleomycin (administered subcutaneously to BALB/c mice for 21 days), bleomycin and fostamatinib (mice fed with chow containing a Syk inhibitor for 21 days), and fostamatinib alone groups. Skin and lung tissue specimens were obtained and evaluated histologically. RESULTS: Treatment with fostamatinib significantly reduced skin thickness and fibrosis. Mice treated with fostamatinib also displayed less fibrosis and inflammation in the lung tissue. Following fostamatinib treatment, Syk, phospho-Syk, and TGF-ß expression decreased in both skin and lung tissues. CONCLUSIONS: The Syk inhibitor fostamatinib prevented bleomycin-induced fibrosis and inflammation in the skin and in the lung. The anti-fibrotic effect of fostamatinib is linked to reduced Syk phosphorylation and TGF-ß expression. The Syk pathway appears as a potential molecular target for therapeutic intervention in SSc.
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Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Oxazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Fibrosis Pulmonar/prevención & control , Piridinas/farmacología , Esclerodermia Sistémica/prevención & control , Piel/efectos de los fármacos , Aminopiridinas , Animales , Bleomicina , Citoprotección , Modelos Animales de Enfermedad , Inmunoglobulina E/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Pulmón/enzimología , Pulmón/inmunología , Pulmón/patología , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones Endogámicos C57BL , Morfolinas , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/patología , Pirimidinas , Receptores Fc/metabolismo , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/enzimología , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/patología , Transducción de Señal/efectos de los fármacos , Piel/enzimología , Piel/inmunología , Piel/patología , Quinasa Syk , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine or by inactivating ATP-binding cassette transporter A1 (ABCA1) ameliorates murine SSc. METHODS: First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo. SSc was induced in BALB/c mice by daily intradermal injection of HOCl. Mice were simultaneously treated daily with pantethine by oral gavage. RESULTS: In vitro, pantethine inhibited MP shedding from tumor necrosis factor-stimulated ECs and abrogated MP-induced oxidative and nitrosative stresses in ECs and fibroblasts. Ex vivo, pantethine also restored redox homeostasis in fibroblasts from mice with SSc. In vivo, mice with SSc displayed skin and lung fibrosis associated with increased levels of circulating MPs and markers of oxidative and endothelial stress, which were normalized by administration of pantethine or inactivation of ABCA1. CONCLUSION: Pantethine is a well-tolerated molecule that represents a potential treatment of human SSc.
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Micropartículas Derivadas de Células/efectos de los fármacos , Micropartículas Derivadas de Células/patología , Células Endoteliales/patología , Panteteína/análogos & derivados , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/prevención & control , Transportador 1 de Casete de Unión a ATP/deficiencia , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Administración Oral , Animales , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Homeostasis/efectos de los fármacos , Ácido Hipocloroso/administración & dosificación , Ácido Hipocloroso/efectos adversos , Técnicas In Vitro , Inyecciones Intradérmicas , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacos , Panteteína/administración & dosificación , Panteteína/farmacología , Panteteína/uso terapéutico , Esclerodermia Sistémica/inducido químicamente , Resultado del TratamientoRESUMEN
OBJECTIVE: Bleomycin-induced fibrosis and the tight skin (TSK/+) mouse are well-established experimental murine models of human systemic sclerosis (SSc). Growing evidence has demonstrated the pivotal role of Toll-like receptors (TLRs) in several autoimmune inflammatory diseases, including SSc. This study was undertaken to determine the role of TLR-4 in the fibrotic processes in these murine models. METHODS: We generated a murine model of bleomycin-induced SSc using TLR-4(-/-) mice and TLR-4(-/-) ;TSK/+ mice. The mechanisms by which TLR-4 contributes to pathologic tissue fibrosis were investigated in these 2 models by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and flow cytometry. RESULTS: Dermal and lung fibrosis was attenuated in bleomycin-treated TLR-4(-/-) mice compared with their wild-type counterparts. Inflammatory cell infiltration, expression of various inflammatory cytokines, and pathologic angiogenesis induced by bleomycin treatment were suppressed with TLR-4 deletion. Furthermore, the increased expression of interleukin-6 (IL-6) in fibroblasts, endothelial cells, and immune cells in response to bleomycin in vivo and to lipopolysaccharide in vitro was notably abrogated in the absence of TLR-4. Moreover, TLR-4 deletion was associated with alleviated B cell activation and skew toward a Th2/Th17 response against bleomycin treatment. Importantly, in TSK/+ mice, another SSc murine model, TLR-4 abrogation attenuated hypodermal fibrosis. CONCLUSION: These results indicate the pivotal contribution of TLR-4 to the pathologic tissue fibrosis of SSc murine models. Our results indicate the critical role of TLR-4 signaling in the development of tissue fibrosis, suggesting that biomolecular TLR-4 targeting might be a potential therapeutic approach to SSc.
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Esclerodermia Sistémica/prevención & control , Esclerodermia Sistémica/fisiopatología , Piel/patología , Receptor Toll-Like 4/deficiencia , Animales , Bleomicina/efectos adversos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis/patología , Fibrosis/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/fisiopatología , Esclerodermia Sistémica/inducido químicamente , Transducción de Señal/fisiología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/fisiologíaRESUMEN
Cellular abelson (c-Abl), a non-receptor tyrosine kinase, is an important molecule in the pathogenesis of systemic sclerosis. There have been reports of beneficial effects of pharmacological tyrosine kinase inhibitors, such as imatinib mesylate, on fibrosis. However, these inhibitors affect multiple tyrosine kinases including c-Abl, c-kit, and platelet-derived growth factor receptor. The effects of selective inhibition of c-Abl using small interfering RNA (siRNA) on dermal fibrosis have not yet been explored. The aim of this study is to evaluate whether specific inhibition of c-Abl by siRNA can influence the transforming growth factor-ß1 (TGF-ß1)-induced fibrotic responses. Dermal fibroblasts from systemic sclerosis patients and healthy controls were transfected with c-Abl siRNA. The expression levels of collagen type I, fibronectin, connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) were measured at both the mRNA and protein levels in the absence or presence of TGF-ß1 pro-fibrotic cytokine. In healthy dermal fibroblasts, the expression of collagen type 1, fibronectin, α-SMA, and CTGF mRNAs and proteins that were upregulated after stimulation with TGF-ß1 was markedly decreased by c-Abl siRNA. Silencing of c-Abl via siRNA efficiently reduced the basal synthesis of collagen type I, fibronectin, α-SMA, and CTGF mRNAs and proteins in systemic sclerosis fibroblasts, but it had no effect on the baseline expression of these genes and proteins in healthy dermal fibroblasts. In conclusion, specific c-Abl gene silencing using siRNA effectively reduced fibrosis-related gene expression. Inhibition of c-Abl by siRNA may be a potential therapeutic approach for fibrotic diseases such as systemic sclerosis.
Asunto(s)
Silenciador del Gen/fisiología , Proteínas Proto-Oncogénicas c-abl/genética , ARN Interferente Pequeño/genética , Esclerodermia Sistémica/prevención & control , Actinas/genética , Actinas/metabolismo , Adulto , Western Blotting , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Transfección , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Introducción. La esclerodermia es una enfermedad rara, de la cual existe información limitada en América Latina. Estudios preliminares en genética muestran que la ascendencia de República Dominicana tiene fuerte influencia africana, lo cual podría modular la expresión de la enfermedad. El propósito de este estudio es describir las características clínicas y demográficas de esclerodermia en una serie de pacientes dominicanos. Materiales y métodos. Se seleccionaron los pacientes que cumplieron con los criterios del EULAR/ACR para esclerosis sistémica de la base de datos del servicio de reumatología de un centro terciario. Se definieron los subtipos de esclerodermia de acuerdo a la clasificación EULAR. La información clínica y demográfica al momento del diagnóstico fue obtenida de forma retrospectiva de los expedientes médicos. Resultados. La prevalencia fue estimada de 9,3 por millón de habitantes. Veinte y seis pacientes entraron al estudio. La edad media al momento del primer síntoma fue 32,6 ± 15 años; el 68% de los pacientes tenía 40 años de edad o menos cuando aparecieron los síntomas. El 73,1% de los pacientes fue de sexo femenino, con una relación mujer:hombre 2,7:1. Los sistemas orgánicos más afectados fueron el pulmonar y el gastrointestinal; la afectación renal fue rara. Los anticuerpos anti-Scl-70 se encontraron positivos en el 64% de los casos y, en 2 casos, en coexistencia con anticentrómero. Conclusiones. La prevalencia de esclerosis sistémica es menor en la población dominicana que la reportada internacionalmente. La edad de inicio de la enfermedad parece ser menor en la población dominicana que la reportada en la literatura. Un patrón distinto de autoanticuerpos es observado en esta población (AU)
Introduction. Scleroderma is a rare disease with limited data in Latin America. Preliminary genetic studies suggest a strong African ascendance in the Dominican Republic, which could modulate the expression of the disease. The objective of this study is to describe the clinical and demographic characteristics of scleroderma in a series of 26 Dominican patients. Materials and methods. Patients who fulfilled the EULAR/ACR criteria for scleroderma were selected from the Rheumatology Department of a tertiary health center; systemic sclerosis subtypes were defined according to the EULAR classification. Clinical and demographic information was obtained retrospectively from clinical records. Results. Mean age at time of onset was 32.6±15 years; 68% of patients had 40 years of age or less. 73% of patients were females, with a female:male ratio of 2.7:1. The most affected systems were pulmonary and gastrointestinal; renal affection was scarce. Anti-Scl-70 antibodies were positive in 64% of patients, sometimes in coexistence with anti-centromere antibodies. Conclusions. The prevalence of systemic sclerosis is lower in the Dominican population than was reported elsewhere. The age of onset of the disease seems to be lower in the Dominican population than that reported in literature. A different pattern of autoantibodies is observed in this population (AU)