RESUMO
Erdheim-Chester disease(E-CD)is a rare pathology characterized by systematic granulomatosis that occasionally involves the central nervous system. We report about a 68-year-old woman with E-CD who presented with right-side visual disturbance. Magnetic resonance imaging showed a suprasellar tumor that elevated the right optic nerve and involved the right internal carotid and right anterior choroidal arteries. The tumor was partially resected via a trans-Sylvian approach and was histologically diagnosed as a granuloma. Considering the abnormal findings of postoperative X-ray and 99 mTc bone scintigraphy of the long bones, the pathology was diagnosed as E-CD. After surgery, her right-side visual disturbances disappeared. However, 1 year later, she died of systemic infection and heart failure. Histological autopsy findings indicated numerous yellowish nodules in the heart, lung, and kidney with pericardial and pleural effusions and whole-body granulomatosis, including the brain. E-CD is a rare but critical disease. This pathological entity should be considered when encountering cases of intracranial granuloma to ensure its early diagnosis and appropriate treatment. Surgical resection of intracranial granulomas in patients with E-CD may promptly improve neurological dysfunction.
Assuntos
Doença de Erdheim-Chester/diagnóstico por imagem , Idoso , Encéfalo , Feminino , Granuloma , Humanos , Imageamento por Ressonância Magnética , RadiografiaRESUMO
Subcortical bleeding from brain tumors is not rare. In the majority of cases, tumors are revealed within a few months after bleeding. We herein report a relatively rare case of glioblastoma(GBM)that appeared one year after the removal of a subcortical hematoma. A 70-year-old woman suddenly began experiencing headache, vomiting, and aphasia. CT revealed a subcortical hematoma in the left superior temporal lobe and subarachnoid bleeding. Neither aneurysms nor abnormal signs suggesting a malignant tumor were noted during cerebral angiography. The hematoma was completely removed via craniotomy, and she was discharged with no neurological deficit.(MRI performed seven months after the surgery showed neither space-occupying lesions in the left temporal lobe nor brain edema. Twelve months after the initial surgery, she had aphasia again. CT and MRI revealed an enhanced mass lesion in the left temporal lobe. Positron emission tomography findings strongly indicated the presence of a malignant tumor. Histology of the tumor after removal showed GBM HDH-1 wild-type with an MIB-1 labelling index of approximately 50%. After the surgery, she underwent extensive local radiation therapy(50 Gy)with chemotherapy(temozolomide). The pathological mechanism underlying the appearance of GBM at the site where subcortical bleeding was previously observed is unclear. GBM may have caused bleeding or may have originated from the brain tissue that was damaged during the first surgery. Follow-up using neuroimaging for one year may be needed when subcortical bleeding is observed.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Hematoma , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Hematoma/complicações , Hematoma/diagnóstico por imagem , Hematoma/cirurgia , Humanos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. OBJECTIVE: We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin. METHODS: Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg-mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23-injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays. RESULTS: IL-23-injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysis-derived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust TH1, TH2, and also TH17 activation are seen in IL-23-injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a TH1-centered reaction, and flaky tail mice demonstrate a strong TH17 polarization. Flg-mutated mice display filaggrin downregulation without significant inflammation. CONCLUSION: No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23-injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.
Assuntos
Dermatite Atópica/genética , Dermatite de Contato/genética , Perfilação da Expressão Gênica/métodos , Psoríase/genética , Pele/imunologia , Adulto , Idoso , Alérgenos/imunologia , Animais , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Proteínas Filagrinas , Humanos , Interleucina-23/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pessoa de Meia-Idade , Ovalbumina/imunologia , Oxazolona , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Pele/patologia , Análise Serial de Tecidos , Adulto JovemRESUMO
BACKGROUND: Atopic dermatitis (AD) and psoriasis pathogeneses involve skin barrier impairment and immune dysregulation; however, the contribution of B-cell imbalances to these diseases has not yet been determined. OBJECTIVE: We sought to quantify B-cell populations and antibody-secreting cells in the blood of patients with AD, patients with psoriasis, and control subjects. METHODS: We studied 34 adults with moderate-to-severe AD (mean SCORAD score, 65), 24 patients with psoriasis (mean Psoriasis Area and Severity Index score, 16), and 27 healthy subjects using an 11-color flow cytometric antibody panel. IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies of plasmablasts and naive, memory, transitional, and activated B cells. RESULTS: We measured increased CD19(+)CD20(+) B-cell counts in the skin and blood of patients with AD (P < .01). Significantly higher frequencies of chronically activated CD27(+) memory and nonswitched memory B cells were observed in patients with AD (P < .05), with lower values of double-negative populations (4% for patients with AD vs. 7% for patients with psoriasis [P = .001] and 6% for control subjects [P = .02]). CD23 expression was highest in patients with AD and correlated with IgE levels (P < .01) and disease severity (r = 0.6, P = .0002). Plasmablast frequencies and IgE expression were highest in all memory subsets of patients with AD (P < .01). Finally, CD19(+)CD24(++)CD38(++) transitional and CD19(+)CD24(-)CD38(-) new memory B-cell counts were higher in patients with AD versus those in patients with psoriasis (2.8% vs. 1.4% [P = .001] and 9.2% vs. 5.7% [P = .02], respectively). CONCLUSIONS: AD is accompanied by systemic expansion of transitional and chronically activated CD27(+) memory, plasmablast, and IgE-expressing memory subsets. These data create a critical basis for the future understanding of this debilitating skin disease.
Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite Atópica/imunologia , Psoríase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Dermatite Atópica/sangue , Feminino , Humanos , Imunoglobulina E/sangue , Ativação Linfocitária , Masculino , Pessoa de Meia-IdadeRESUMO
Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases characterized by immune-mediated inflammation and abnormal keratinocyte differentiation. Although T-cell infiltration characterizes both diseases, T-cell polarization differs. Psoriasis is currently the best model for translational medicine because many targeted therapeutics have been developed and testing of targeted therapeutics has cemented psoriasis as IL-23/TH17 polarized. In patients with AD, although therapeutic development is approximately a decade behind that in patients with psoriasis, there is now active development and testing of targeted therapeutics against various immune axes (TH2, TH22, and IL-23/TH17). These clinical trials and subsequent molecular analyses using human samples will be able to clarify the relative roles of polar cytokines in patients with AD.
Assuntos
Anti-Inflamatórios/uso terapêutico , Fatores Biológicos/uso terapêutico , Dermatite/tratamento farmacológico , Dermatite/etiologia , Dermatite/diagnóstico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etiologia , Humanos , Psoríase/tratamento farmacológico , Psoríase/etiologia , Pesquisa Translacional BiomédicaRESUMO
BACKGROUND: Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17(+)-producing cell counts in Asian patients with AD. OBJECTIVE: We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. METHODS: We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). RESULTS: Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD (P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. TH2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. CONCLUSION: The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component. The relative pathogenic contributions of the TH17 and TH2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics.
Assuntos
Dermatite Atópica/etnologia , Dermatite Atópica/imunologia , Psoríase/etnologia , Psoríase/imunologia , Células Th17/imunologia , Adolescente , Adulto , Idoso , Povo Asiático , Diferenciação Celular , Citocinas/metabolismo , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Componente Principal , Pele/imunologia , Pele/patologia , Células Th2/imunologia , População Branca , Adulto JovemRESUMO
BACKGROUND: Identifying differences and similarities between cutaneous lymphocyte antigen (CLA)(+) polarized T-cell subsets in children versus adults with atopic dermatitis (AD) is critical for directing new treatments toward children. OBJECTIVE: We sought to compare activation markers and frequencies of skin-homing (CLA(+)) versus systemic (CLA(-)) "polar" CD4 and CD8 T-cell subsets in patients with early pediatric AD, adults with AD, and control subjects. METHODS: Flow cytometry was used to measure CD69/inducible costimulator/HLA-DR frequency in memory cell subsets, as well as IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines, defining TH1/cytotoxic T (TC) 1, TH2/TC2, TH9/TC9, TH17/TC17, and TH22/TC22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children less than 5 years old and 42 adults with well-characterized moderate-to-severe AD, as well as age-matched control subjects (17 children and 25 adults). RESULTS: Selective inducible costimulator activation (P < .001) was seen in children. CLA(+) TH2 T cells were markedly expanded in both children and adults with AD compared with those in control subjects, but decreases in CLA(+) TH1 T-cell numbers were greater in children with AD (17% vs 7.4%, P = .007). Unlike in adults, no imbalances were detected in CLA(-) T cells from pediatric patients with AD nor were there altered frequencies of TH22 T cells within the CLA(+) or CLA(-) compartments. Adults with AD had increased frequencies of IL-22-producing CD4 and CD8 T cells within the skin-homing population, compared with controls (9.5% vs 4.5% and 8.6% vs 2.4%, respectively; P < .001), as well as increased HLA-DR activation (P < .01). CONCLUSIONS: These data suggest that TH2 activation within skin-homing T cells might drive AD in children and that reduced counterregulation by TH1 T cells might contribute to excess TH2 activation. TH22 "spreading" of AD is not seen in young children and might be influenced by immune development, disease chronicity, or recurrent skin infections.
Assuntos
Dermatite Atópica/imunologia , Interleucinas/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Adulto , Idoso , Antígenos de Diferenciação de Linfócitos T/metabolismo , Separação Celular , Criança , Pré-Escolar , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Ativação Linfocitária , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Equilíbrio Th1-Th2 , Adulto Jovem , Interleucina 22RESUMO
BACKGROUND: Alopecia areata (AA) is a common T cell-mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on TH1/IFN-γ responses, several observations support a shared genetic background between AA and atopy. OBJECTIVE: We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. METHODS: We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). RESULTS: We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs [297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in TH1/interferon markers (IFNG and CXCL10/CXCL9) were those noted in TH2 (IL13, CCL18, CCL26, thymic stromal lymphopoietin, and periostin), TH9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in TH17/TH22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85). CONCLUSIONS: Our data associate the AA signature with TH2, TH1, IL-23, and IL-9/TH9 cytokine activation, suggesting consideration of anti-TH2, anti-TH1, and anti-IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways.
Assuntos
Alopecia em Áreas/imunologia , Dermatite Atópica/imunologia , Psoríase/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Biomarcadores/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Feminino , Humanos , Interleucina-23/metabolismo , Queratinas Específicas do Cabelo/genética , Queratinas Específicas do Cabelo/metabolismo , Ativação Linfocitária , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Transcriptoma , 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
Psoriasis, a chronic inflammatory dermatosis, is frequently associated with metabolic disorders, suggesting that adipokines are involved in its pathogenesis. We recently reported that the adipokine visfatin activates NF-κB and STAT3 in keratinocytes. Antimicrobial peptide expression is enhanced in psoriatic lesions and may promote disease development. Here, we investigated the effects of visfatin on antimicrobial peptide expression. In vitro, visfatin enhanced basal and tumor necrosis factor-α (TNF-α)-induced mRNA expression and secretion of cathelicidin antimicrobial peptide (CAMP), and enhanced TNF-α-induced human ß-defensin-2 (hBD-2), hBD-3, and S100A7 mRNA expression and secretion in human keratinocytes. siRNAs targeting CCAAT/enhancer-binding protein-α (C/EBPα) suppressed visfatin-induced and visfatin plus TNF-α-induced CAMP production. siRNAs targeting NF-κB p65 and STAT3 suppressed visfatin plus TNF-α-induced hBD-2 and S100A7 production. siRNAs targeting c-Jun and STAT3 suppressed visfatin plus TNF-α-induced hBD-3 production. Visfatin and/or TNF-α enhanced C/EBP transcriptional activity and C/EBPα phosphorylation, which were suppressed by p38 mitogen-activated protein kinase (MAPK) inhibition. Visfatin and/or TNF-α induced p38 MAPK phosphorylation. Visfatin increased mRNA and protein expression of CAMP, hBD-2, hBD-3, and S100A7 orthologs in murine imiquimod-treated skin, mimicking psoriasis. In conclusion, visfatin enhances CAMP, hBD-2, hBD-3, and S100A7 production in human keratinocytes and their orthologs in murine imiquimod-treated psoriatic skin. Visfatin may potentiate the development of psoriasis via antimicrobial peptides.
Assuntos
Catelicidinas/biossíntese , Queratinócitos/metabolismo , Nicotinamida Fosforribosiltransferase/farmacologia , Psoríase/patologia , Proteínas S100/metabolismo , Pele/metabolismo , beta-Defensinas/metabolismo , Aminoquinolinas , Animais , Peptídeos Catiônicos Antimicrobianos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Humanos , Imiquimode , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptor de Insulina/metabolismo , Proteína A7 Ligante de Cálcio S100 , Fator de Transcrição STAT3/metabolismo , Pele/patologia , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/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: 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
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: 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
Decoy receptor 3 (DcR3) is associated with autoimmunity and altered angiogenesis in certain pathological conditions. We herein measured serum DcR3 levels in 51 patients with systemic sclerosis (SSc) and 19 healthy controls and evaluated their clinical significance in this disorder. Serum DcR3 levels were significantly higher in diffuse cutaneous SSc (dcSSc) patients than in limited cutaneous SSc patients and in healthy controls. In dcSSc, serum DcR3 levels were significantly elevated in patients with disease duration of ≤6 years compared with healthy controls, but not in those with disease duration of >6 years. Serum DcR3 levels correlated negatively with the percentage of predicted diffusion lung capacity for carbon monoxide and positively with right ventricular systolic pressure. Furthermore, serum DcR3 levels positively correlated with C-reactive protein, erythrocyte sedimentation rate and immunoglobulin G. Collectively, the elevation of serum DcR3 levels is associated with the development of pulmonary arterial hypertension and systemic inflammation in SSc.