RESUMO
CXCL13, a chemokine for B cells, follicular T cells, T helper 17 cells, and regulatory T cells, is reported to contribute to the development of systemic sclerosis (SSc), reflecting aberrant activation of immune system. To better understand the role of CXCL13 in SSc, we investigated the influence of Fli1 deficiency, a potential predisposing factor of this disease, on CXCL13 expression and assessed the clinical correlation of serum CXCL13 levels by multivariate regression analysis. Haploinsufficient loss of Fli1 remarkably induced CXCL13 expression in murine peritoneal macrophages, while gene silencing of FLI1 did not affect the expression of CXCL13 in human dermal fibroblasts and human dermal microvascular endothelial cells. Serum CXCL13 levels were elevated in SSc patients compared with healthy controls and correlated positively with skin score and negatively with pulmonary function test results. SSc patients with elevated serum CXCL13 levels had longer disease duration, diffuse cutaneous involvement, interstitial lung disease (ILD), heart involvement, pulmonary arterial hypertension, Raynaud's phenomenon, pitting scars, digital ulcers, telangiectasia, and high serum IgG levels more frequently than the other patients. In particular, serum CXCL13 levels were associated with ILD and digital ulcers by multivariate regression analysis. Taken together, these results indicate that CXCL13 expression is upregulated by Fli1 deficiency in macrophages, potentially contributing to the development of tissue fibrosis, vasculopathy and immune activation in SSc, especially ILD and digital ulcers.
Assuntos
Quimiocina CXCL13/sangue , Doenças Pulmonares Intersticiais/sangue , Pulmão/patologia , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/sangue , Úlcera Cutânea/sangue , Pele/patologia , Idoso , Animais , Células Cultivadas , Quimiocina CXCL13/genética , Células Endoteliais , Feminino , Fibroblastos , Fibrose , Dedos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Inativação Gênica , Humanos , Lipopolissacarídeos/farmacologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , RNA Mensageiro/metabolismo , Doença de Raynaud/sangue , Doença de Raynaud/etiologia , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Úlcera Cutânea/etiologiaRESUMO
Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5(-/-)) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5(-/-) mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.
Assuntos
Fatores Reguladores de Interferon/fisiologia , Escleroderma Sistêmico/fisiopatologia , Receptor 4 Toll-Like/fisiologia , Animais , Linfócitos B/imunologia , Feminino , Fatores Reguladores de Interferon/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The insufficiency of Friend leukaemia virus integration 1 (Fli1), a member of the Ets family transcription factors, is implicated in the pathogenesis of vasculopathy associated with systemic sclerosis (SSc). Fli1 deficiency accelerates early steps of angiogenesis, including detachment of pre-existing pericytes and extracellular matrix degradation by endothelial proteinases, but the impact of Fli1 deficiency on the other steps of angiogenesis has not been investigated. Therefore, we evaluated the effect of Fli1 deficiency on migration, proliferation, cell survival and tube formation of human dermal microvascular endothelial cells (HDMECs). HDMECs transfected with FLI1 siRNA exhibited a greater migratory property in scratch assay and transwell migration assay and a higher proliferation rate in BrdU assay than HDMECs transfected with non-silencing scrambled RNA. In flow cytometry-based apoptosis assay, FLI1 siRNA-transduced HDMECs revealed the decreased number of annexin and propidium iodide-double-positive apoptotic cells compared with control cells, reflecting the promotion of cell survival. On the other hand, tubulogenic activity on Matrigel was remarkably suppressed in Fli1-deficient HDMECs relative to control cells. These results indicate that Fli1 deficiency promotes migration, proliferation and cell survival, while abating tube formation of endothelial cells, suggesting that Fli1 deficiency is potentially attributable to the development of both proliferative obliterative vasculopathy (occlusion of arterioles and small arteries) and destructive vasculopathy (loss of small vessels) characteristic of SSc vasculopathy.
Assuntos
Células Endoteliais/fisiologia , Neovascularização Fisiológica/genética , Proteína Proto-Oncogênica c-fli-1/deficiência , Proteína Proto-Oncogênica c-fli-1/genética , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Inativação Gênica/fisiologia , Humanos , RNA Interferente PequenoRESUMO
OBJECTIVES: Intravenous pulse cyclophosphamide (IVCY) is the first-line treatment for systemic sclerosis-associated interstitial lung disease (SSc-ILD). So far, there is no useful predictive marker for IVCY efficacy against SSc-ILD, although potential candidates are parameters reflecting vascular activation. Since plasma levels of plasmin-α2-plasmin inhibitor complex (PIC) serve as a potential biomarker of SSc vasculopathy, we evaluated the usefulness of plasma PIC levels as an indicator for IVCY efficacy against SSc-ILD. METHODS: We measured plasma PIC levels in 23 patients with active SSc-ILD and 20 patients with stabilized SSc-ILD, and also retrospectively studied traceable data of patients with active SSc-ILD during IVCY therapy. RESULTS: Plasma PIC levels were significantly elevated in patients with active SSc-ILD as compared to patients with stabilized SSc-ILD. Among patients with active SSc-ILD, baseline plasma PIC concentrations were significantly higher in patients responsive to IVCY than in those refractory to IVCY. After the entire six infusions, plasma PIC levels were significantly decreased compared with baseline in the responders, while not in the nonresponders. In the responders, plasma PIC levels were remarkably decreased after a couple of infusions. Regarding the changes of parameters by the entire infusions, Δ plasma PIC levels correlated positively with Δ serum KL-6 levels and inversely with Δ the percentage of predicted vital capacity. CONCLUSIONS: The elevation of baseline plasma PIC levels and the rapid decrease in plasma PIC levels during a couple of infusions may predict the efficacy of the entire IVCY therapy against SSc-ILD.
Assuntos
Antirreumáticos/uso terapêutico , Ciclofosfamida/uso terapêutico , Fibrinolisina/metabolismo , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/complicações , alfa 2-Antiplasmina/metabolismo , Biomarcadores/sangue , Feminino , Humanos , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escleroderma Sistêmico/sangue , Resultado do TratamentoRESUMO
Cathepsin L (CTSL) is a lysosomal proteolytic enzyme involved in inflammation and vascular and extracellular matrix remodelling, which are the three cardinal pathological events associated with systemic sclerosis (SSc). To elucidate the potential role of CTSL in the development of SSc, we here investigated CTSL expression in the lesional skin of patients with SSc and SSc animal models and the clinical correlation of serum CTSL levels. CTSL expression was elevated in dermal small vessels of SSc patients compared with those of healthy controls. Consistently, CTSL mRNA levels were increased in SSc lesional skin samples, but not in cultivated SSc dermal fibroblasts, compared with corresponding control samples from healthy individuals. Serum CTSL levels were significantly higher in SSc patients than in healthy controls and inversely correlated with skin score. Furthermore, the elevation of serum CTSL levels was linked to SSc vasculopathy. Supporting these results, Ctsl mRNA levels were decreased in the skin of bleomycin-treated mice, an SSc animal model recapitulating its fibrotic aspect, and CTSL expression was enhanced in dermal small vessels of endothelial cell-specific Fli1 knockout mice, reminiscent of SSc vasculopathy. Importantly, gene silencing of FLI1 induced CTSL mRNA expression and Fli1 occupied the CTSL promoter in human dermal microvascular endothelial cells. Collectively, these results suggest that endothelial CTSL up-regulation partially due to Fli1 deficiency may contribute to the development of vasculopathy, while the decrease in dermal CTSL expression is likely associated with dermal fibrosis in SSc.
Assuntos
Catepsina L/metabolismo , Regulação da Expressão Gênica , Escleroderma Sistêmico/metabolismo , Pele/patologia , Doenças Vasculares/metabolismo , Adulto , Idoso , Animais , Biópsia , Bleomicina/química , Catepsina L/sangue , Feminino , Fibroblastos/metabolismo , Fibrose , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-fli-1/genética , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/sangue , Pele/metabolismo , Doenças Vasculares/sangue , Adulto JovemRESUMO
Systemic sclerosis (SSc) is characterized by disturbed blood circulation. The effect of ambrisentan, an endothelin-A receptor-selective antagonist, on impaired peripheral circulation in SSc remains largely elusive. Here we show SSc patients, whose clinical symptoms such as cyanosis and Raynaud's phenomenon, were ameliorated by the treatment with ambrisentan. Additionally, objective evaluations with thermography showed improvement of hand coldness in steady-state and cold challenge tests. Ambrisentan might have a potential to improve peripheral circulation in SSc.
Assuntos
Antagonistas do Receptor de Endotelina A/uso terapêutico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Doença de Raynaud/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVES: Chemerin is a member of adipocytokines with a chemoattractant effect on plasmacytoid dendritic cells and macrophages and pro-angiogenic properties. We investigated the potential role of chemerin in the development of SSc. METHODS: Chemerin expression was evaluated by immunostaining and/or real-time quantitative RT-PCR in human and murine skin. The mechanisms regulating chemerin expression in dermal fibroblasts and endothelial cells were examined using the gene silencing technique and chromatin immunoprecipitation. Serum chemerin levels were determined by ELISA in 64 SSc patients and 19 healthy subjects. RESULTS: In SSc lesional skin, chemerin was up-regulated in small blood vessels, while it was down-regulated in fibroblasts surrounded with thickened collagen bundles. The decreased expression of chemerin was significantly reversed by TGF-ß1 antisense oligonucleotide in cultured SSc dermal fibroblasts and chemerin expression was markedly decreased in dermal fibroblasts of bleomycin-treated mice. Gene silencing of transcription factor Fli1, which binds to the chemerin promoter, induced chemerin expression in human dermal microvascular endothelial cells and Fli1(+/-) mice exhibited elevated chemerin expression in dermal blood vessels. Serum chemerin levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. In SSc patients with normal renal function, patients with digital ulcers had higher serum chemerin levels than those without. CONCLUSION: Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-ß, while it is up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. Increased chemerin expression in dermal blood vessels may be associated with the development of digital ulcers in SSc.
Assuntos
Quimiocinas/metabolismo , Células Endoteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/complicações , Úlcera/etiologia , Úlcera/metabolismo , Idoso , Animais , Bleomicina/efeitos adversos , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Dedos , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/farmacologia , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/irrigação sanguínea , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismo , Úlcera/induzido quimicamenteRESUMO
CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1(+/-) mice and partially in those of endothelial cell-specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc.
Assuntos
Vasos Sanguíneos/fisiopatologia , Proteína Rica em Cisteína 61/metabolismo , Endotélio/metabolismo , Dedos/fisiopatologia , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/metabolismo , Úlcera Cutânea/metabolismo , Idoso , Animais , Vasos Sanguíneos/metabolismo , Proteína Rica em Cisteína 61/sangue , Epigênese Genética , Feminino , Fibroblastos/metabolismo , Inativação Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neovascularização Patológica , Proteína Proto-Oncogênica c-fli-1/genética , Pele/irrigação sanguínea , Pele/metabolismoRESUMO
Angiopoietin-like protein 3 (ANGPTL3), which is part of a family of secreted glycoproteins that are structurally similar to angiopoietins, is principally expressed in the liver and is involved in lipid metabolism and angiogenesis. The aim of this study was to determine the clinical significance of serum ANGPTL3 levels, measured with a specific enzyme-linked immunosorbent assay, in patients with systemic sclerosis. Serum ANGPTL3 levels correlated positively with skin score in diffuse cutaneous systemic sclerosis with a disease duration ≤ 6 years. Furthermore, the prevalence of digital ulcers was significantly higher in patients with elevated serum ANGPTL3 levels than in other patients. Moreover, among patients excluding diffuse cutaneous systemic sclerosis with disease duration ≤ 6 years, serum ANGPTL3 levels correlated positively with estimated right ventricular systolic pressure. In conclusion, ANGPTL3 may contribute to the development of progressive skin sclerosis and proliferative obliterative vasculopathy, such as digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, in systemic sclerosis.
Assuntos
Angiopoietinas/sangue , Dedos/fisiopatologia , Hipertensão Pulmonar/sangue , Escleroderma Sistêmico/sangue , Úlcera Cutânea/sangue , Adulto , Idoso , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/fisiopatologia , Úlcera Cutânea/fisiopatologia , Sístole/fisiologia , Função Ventricular Direita/fisiologiaRESUMO
Our latest studies demonstrated the potential role of adipocytokines, including adiponectin, visfatin, retinol binding protein-4, and apelin, in the pathogenesis of systemic sclerosis (SSc). Given that resistin is another member of adipocytokines with pro-inflammatory and pro-angiogenic properties, we measured serum resistin levels by enzyme-linked immunosorbent assay in 52 SSc and 19 control subjects and evaluated their clinical correlation. Since serum resistin levels greatly and inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction [r = -0.78, p < 0.05 (n = 9)], we evaluated the clinical correlation of serum resistin levels in SSc patients with normal renal function (n = 43). Although serum resistin levels were comparable between diffuse cutaneous SSc (n = 22), limited cutaneous SSc (n = 21), and control subjects (n = 19) [median (25-75 percentiles); 18.7 ng/ml (13.3-48.0), 23.3 ng/ml (12.9-54.1), and 22.9 ng/ml (9.4-36.7), respectively], the prevalence of elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum resistin levels than in those with normal levels [67 % (4/6) vs. 16 % (6/37), p < 0.05], and serum resistin levels were significantly increased in SSc patients with elevated RVSP (n = 10) as compared to those with normal RVSP (n = 33) [52.1 ng/ml (20.8-117.5) vs. 18.5 ng/ml (12.2-46.2), p < 0.05]. Thus, serum resistin levels may serve as a useful marker for pulmonary vascular involvement in SSc, suggesting a possible contribution of resistin to the pathogenesis of pulmonary arterial hypertension associated with SSc.
Assuntos
Hipertensão Pulmonar/etiologia , Artéria Pulmonar/fisiopatologia , Resistina/sangue , Escleroderma Sistêmico/sangue , Pressão Arterial , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/sangue , Esclerodermia Difusa/complicações , Esclerodermia Difusa/diagnóstico , Esclerodermia Limitada/sangue , Esclerodermia Limitada/complicações , Esclerodermia Limitada/diagnóstico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Regulação para Cima , Função Ventricular Direita , Pressão VentricularRESUMO
OBJECTIVE: To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). METHODS: Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. RESULTS: Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = -0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). CONCLUSION: The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.
Assuntos
Artéria Braquial/fisiopatologia , Endotélio Vascular/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Escleroderma Sistêmico/fisiopatologia , Vasodilatação/fisiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Cathepsin V (CTSV) is a proteolytic enzyme potentially modulating angiogenic processes, collagen degradation and keratinocyte differentiation. We aimed to investigate the clinical association of serum CTSV levels and the mechanism by which CTSV expression is altered in SSc. METHODS: Serum CTSV levels were determined by ELISA in 51 SSc and 18 healthy subjects. CTSV expression was evaluated by immunostaining in SSc and normal skin and by RT-real-time PCR in normal and SSc dermal fibroblasts, normal dermal fibroblasts treated with TGF-ß1 or Fli1 siRNA and human dermal microvascular endothelial cells (ECs) treated with Fli1 siRNA. RESULTS: Serum CTSV levels were significantly lower in dcSSc and lcSSc patients than in healthy controls. In early-stage dcSSc, serum CTSV levels were remarkably and uniformly decreased compared with healthy controls. The decrease in serum CTSV levels in mid- and late-stage dcSSc and in lcSSc was linked to the development of proliferative vasculopathy. CTSV expression was decreased in microvascular ECs, pericytes/vascular smooth muscle cells and keratinocytes of dcSSc and lcSSc skin and in dermal fibroblasts of dcSSc skin compared with control skin. Consistently, CTSV expression was decreased in cultured dermal fibroblasts from early-stage dcSSc. Furthermore, mRNA levels of the CTSV gene were significantly decreased in normal fibroblasts treated with TGF-ß1 or Fli1 siRNA and in human dermal microvascular ECs treated with Fli1 siRNA. CONCLUSION: Loss of CTSV expression may contribute to the development of fibrosis, vasculopathy and the altered phenotype of keratinocytes in SSc.
Assuntos
Catepsinas/genética , Cisteína Endopeptidases/genética , Neovascularização Patológica/genética , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/genética , Adulto , Idoso , Biópsia por Agulha , Estudos de Casos e Controles , Catepsinas/metabolismo , Cisteína Endopeptidases/metabolismo , Progressão da Doença , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Prognóstico , RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Esclerodermia Difusa/genética , Esclerodermia Difusa/patologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Visfatin is a member of the adipocytokines with pro-fibrotic, pro-inflammatory and immunomodulating properties potentially implicated in the pathogenesis of certain fibrotic and inflammatory autoimmune diseases. In this study, we investigated THE CLINICAL SIGNIFICANCE OF SERUM VISFATIN LEVELS AND ITS CONTRIBUTION TO THE DEVELOPMENTAL PROCESS IN SSC. METHODS: Serum visfatin levels were determined by a specific ELISA in 57 SSc patients and 19 healthy controls. The mRNA levels of target genes were determined in normal and SSc fibroblasts by real-time RT-PCR. The levels of IL-12p70 produced by THP-1 cells were measured by a specific ELISA. RESULTS: Serum visfatin levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc and healthy controls. The only finding in a series of analyses regarding the correlation of serum visfatin levels with clinical symptoms and laboratory data was the significantly longer disease duration in dcSSc with elevated serum visfatin levels than in those with normal levels. Consistently, serum visfatin levels were significantly elevated in late-stage dcSSc (disease duration >6 years), but not in early and mid-stage dcSSc compared with healthy controls. In in vitro experiments, visfatin reversed the pro-fibrotic phenotype of SSc dermal fibroblasts and induced the expression of IL-12p70 in THP-1 cells treated with IFN-γ plus lipopolysaccharide. CONCLUSION: Visfatin may contribute to the resolution of skin sclerosis in late-stage dcSSc via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response.
Assuntos
Fibroblastos/patologia , Nicotinamida Fosforribosiltransferase/fisiologia , Esclerodermia Difusa/terapia , Pele/patologia , Células Th1/imunologia , Estudos de Casos e Controles , Células Cultivadas , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/metabolismo , Humanos , Imunidade Celular , Interleucina-12 , Masculino , Nicotinamida Fosforribosiltransferase/sangue , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Esclerodermia Difusa/imunologia , Esclerodermia Difusa/patologiaRESUMO
A 68-year-old Japanese woman was referred to our hospital with a 1-year history of multiple erosions on the oral mucosa and a few pruritic, bean-sized, reddish-blue plaques on the body. Based on physical examination, pathological findings, and immunofluorescence findings, a diagnosis of lichen planus (LP) was made. Computed tomography scan revealed a thymoma. After thymectomy, cutaneous LP lesions subsided spontaneously. Oral lesions responded well to oral etretinate therapy. We speculate that direct tissue injury by CD8(+) T cells, activated by abnormal regulation of lymphocytes within the thymus, may cause LP.
Assuntos
Etretinato/uso terapêutico , Ceratolíticos/uso terapêutico , Líquen Plano Bucal/tratamento farmacológico , Líquen Plano Bucal/etiologia , Timoma/complicações , Neoplasias do Timo/complicações , Idoso , Feminino , Humanos , Líquen Plano Bucal/diagnóstico , Timoma/diagnóstico , Timoma/terapia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/terapiaRESUMO
OBJECTIVE: To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). METHODS: Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. RESULTS: Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = -0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). CONCLUSION: The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.
RESUMO
OBJECTIVE: To investigate the clinical significance of monitoring serum adiponectin levels during intravenous pulse cyclophosphamide (IVCY) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD). METHODS: Serum adiponectin levels were determined by a specific enzyme-linked immunosorbent assay in eight SSc patients with active ILD who underwent IVCY and 27 healthy controls. In patients, serum samples were drawn the day before each IVCY. RESULTS: Serum adiponectin levels were significantly decreased in SSc patients with active ILD before the first IVCY compared with healthy controls [median (25-75 percentile): 3.21 (2.70-4.19) vs. 7.42 (6.06-10.82) µg/ml; P < 0.01). After the completion of whole IVCY, serum adiponectin levels were significantly increased [17.55 (6.47-39.45) µg/ml; P < 0.05] compared with the initial levels, and this increase significantly correlated with the decrease in ILD scores. Importantly, the dynamics of serum adiponectin levels during the IVCY therapy reflected its efficacy against SSc-ILD over the treatment and the follow-up period. CONCLUSION: The monitoring of serum adiponectin levels during the IVCY treatment may be useful to identify SSc patients with ILD refractory to the treatment and at high risk for exacerbations during the follow-up period.
Assuntos
Adiponectina/sangue , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/sangue , Escleroderma Sistêmico/sangue , Ciclofosfamida/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Imunossupressores/administração & dosagem , Injeções Intravenosas , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: Angiopoietin-2 (Ang2) regulates the transition between vascular quiescence and angiogenesis in a context-dependent manner. In systemic sclerosis (SSc), serum Ang2 levels correlate with its disease activity. Therefore, we investigated the clinical significance of monitoring serum Ang2 levels during intravenous pulse cyclophosphamide (IVCY) therapy in SSc patients with interstitial lung disease (ILD). METHODS: Serum Ang2 levels were determined by a specific enzyme-linked immunosorbent assay in seven SSc patients treated with IVCY and 20 healthy controls. In the patient group, serum samples were drawn the day before each IVCY therapy. RESULTS: Serum Ang2 levels tended to be higher in SSc patients before IVCY than in healthy controls and significantly correlated with KL-6, surfactant protein D, erythrocyte sedimentation rate, and C-reactive protein in SSc patients with ILD. In sera drawn before the last IVCY, Ang2 levels were significantly decreased compared with initial levels. Notably, Δ serum Ang2 levels between baseline and after the first IVCY significantly correlated with Δ ILD score between before and after the entire IVCY therapy (r = 0.90, p < 0.01). CONCLUSION: Monitoring Ang2 levels during IVCY treatment may be useful to evaluate and predict the efficacy of this treatment for SSc-ILD.
Assuntos
Angiopoietina-2/sangue , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/sangue , Escleroderma Sistêmico/sangue , Idoso , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Pessoa de Meia-Idade , Prognóstico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Resultado do TratamentoRESUMO
Intravenous cyclophosphamide pulse therapy (IVCY) exerts its efficacy against interstitial lung disease (ILD) associated with systemic sclerosis (SSc) by restoring vascular injuries as well as aberrant immune activation. We recently experienced two patients with SSc-ILD in whom the values of brachial flow-mediated dilation (FMD) reflected the efficacy of IVCY. We herein report the details of these cases and discuss the potential of FMD to predict and evaluate the effect of IVCY on SSc-ILD.
Assuntos
Tosse/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Dispneia/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Idoso , Tosse/fisiopatologia , Ciclofosfamida/administração & dosagem , Dispneia/fisiopatologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Injeções Intravenosas , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Pessoa de Meia-Idade , Pulsoterapia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Pele/irrigação sanguínea , Pele/patologia , Resultado do Tratamento , Vasodilatação/efeitos dos fármacosRESUMO
Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and T helper (Th)2/Th17 cytokines serve as critical disease drivers. LIGHT is a proinflammatory cytokine promoting IL-6 production in lung fibroblasts and Th1 chemokine expression in dermal fibroblasts (DFs) stimulated with IFN-γ. In this study, we investigated the potential contribution of LIGHT to SSc development using clinical samples and animal models. In SSc-involved skin, LIGHT was upregulated in inflammatory cells, whereas herpesvirus entry mediator (HVEM), a receptor of LIGHT, was downregulated in DFs. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter, and FLI1 small interfering RNA suppressed HVEM expression in normal DFs. In SSc DFs, LIGHT significantly increased IL-6 production, whereas IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with that in normal DFs. Importantly, LIGHT small interfering RNA significantly attenuated bleomycin-induced skin fibrosis, and serum LIGHT levels were elevated in patients with diffuse cutaneous SSc and positively correlated with clinical parameters reflecting skin and pulmonary fibrosis. Taken together, these results suggest that altered response of DFs to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.