RESUMO
OBJECTIVE: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. METHODS: Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. RESULTS: Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor ß (TGFß)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. CONCLUSION: These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFß- and IFN-regulated genes.
Assuntos
Pulmão/metabolismo , Ativação de Macrófagos/genética , Fibrose Pulmonar/genética , Escleroderma Sistêmico/genética , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Adulto , Antígenos/genética , Antígenos/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVE: The physiological and mechanical properties of the skin, the primary tissue affected by systemic sclerosis, depend on the assembly of collagen types I, III and V, which form heterotypic fibers. Collagen V (COLV) regulates heterotypic fiber diameter, and the maintenance of its properties is important for maintaining normal tissue architecture and function. Based on a COLV-induced experimental SSc model, in which overexpression of abnormal COLV was a prominent feature, we assumed that this abnormality could be present in SSc patients and could be correlated to disease duration, skin thickening and disease activity. METHODS: Skin biopsies from 18 patients (6 early-stage and 12 late-stage) and 10 healthy controls were studied. Skin thickening assessment was performed with the Modified Rodnan Skin Score (MRSS), and activity was calculated using the Valentini Disease Activity Index. Morphology, morphometry of COLV deposition in dermis, as well as, quantitative RT-PCR and 3D-reconstruction of the dermal fibroblast culture were performed. RESULTS: Structurally abnormal COLV was overexpressed in SSc skin, mainly in the early stages of the disease, when compared to normal controls and late-stage. A positive correlation between COLV expression and MRSS and disease activity was observed. Collagen V alpha-1 and alpha-2 mRNA expression levels were higher in SSc. Tridimensional reconstruction of SSc dermal heterotypic fibers confirmed the presence of atypical COLV. CONCLUSION: Increased synthesis of abnormal COLV and its correlation with disease stage, activity and MRSS suggest that this collagen can be a possible trigger involved in the pathogenesis of SSc.
Assuntos
Colágeno Tipo V/metabolismo , Derme/metabolismo , Derme/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Adulto , Biópsia , Estudos de Casos e Controles , Colágeno/genética , Colágeno/metabolismo , Colágeno Tipo V/genética , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/genética , Índice de Gravidade de Doença , Pele/metabolismo , Pele/patologia , Adulto JovemRESUMO
The optimal training model for patients with systemic sclerosis (SSc) is unknown. In this study, we aimed to investigate the effects of a 12-week combined resistance and aerobic training program (concurrent training) in SSc patients. Eleven patients with no evidence of pulmonary involvement were recruited for the exercise program. Lower and upper limb dynamic strengths (assessed by 1 repetition maximum [1RM] of a leg press and bench press, respectively), isometric strength (assessed by back pull and handgrip tests), balance and mobility (assessed by the timed up-and-go test), muscle function (assessed by the timed-stands test), Rodnan score, digital ulcers, Rayland's phenomenon, and blood markers of muscle inflammation (creatine kinase and aldolase) were assessed at baseline and after the 12-week program. Exercise training significantly enhanced the 1RM leg press (41%) and 1RM bench press (13%) values and back pull (24%) and handgrip strength (11%). Muscle function was also improved (15%), but balance and mobility were not significantly changed. The time-to-exhaustion was increased (46.5%, p = 0.0004), the heart rate at rest condition was significantly reduced, and the workload and time of exercise at ventilatory thresholds and peak of exercise were increased. However, maximal and submaximal &OV0312;o2 were unaltered (p > 0.05). The Rodnan score was unchanged, and muscle enzymes remained within normal levels. No change was observed in digital ulcers and Raynaud's phenomenon. This is the first study to demonstrate that a 12-week concurrent training program is safe and substantially improves muscle strength, function, and aerobic capacity in SSc patients.
Assuntos
Exercício Físico , Força Muscular/fisiologia , Resistência Física/fisiologia , Treinamento Resistido , Escleroderma Sistêmico/reabilitação , Adulto , Estudos de Coortes , Terapia por Exercício/métodos , Tolerância ao Exercício/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Medição de Risco , Gestão da Segurança , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Interstitial lung disease (ILD) is currently the main cause of death in systemic sclerosis (SSc) and has an unknown pathogenesis. Gastroesophageal reflux (GER) has been strongly implicated as a cause of ILD in several lung diseases, including SSc-ILD. This review summarizes clinical, radiologic, histopathologic, and treatment aspects of GER in SSc-ILD. METHODS: The PubMed database was searched using the following keywords: "systemic sclerosis, scleroderma, interstitial lung disease, and gastroesophageal reflux." The research was limited to English-language studies that included SSc patients with ILD. RESULTS: Pulmonary function tests were related with the presence of GER in several esophageal functional tests (esophageal endoscopy, pH monitoring, and manometric analysis). Regarding the histopathologic data, a pattern called centrilobular fibrosis was described in 21% of 28 lung biopsies, with a bronchocentric distribution and with an intraluminal content resembling gastric fluid. Radiologic evidence of esophageal dilation is very frequent in SSc patients, and consolidation with a patchy distribution was almost exclusively found in SSc patients with centrilobular fibrosis lung pattern. Furthermore, high levels of serum KL-6, a marker of epithelial injury, are indicative of active ILD in SSc disease. CONCLUSIONS: The association of GER with SSc-ILD is strongly supported by several studies. An aggressive treatment for reflux is recommended in all SSc patients with ILD; however, future studies need to be performed to prove a long-term benefit.
Assuntos
Refluxo Gastroesofágico/complicações , Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações , Biópsia , Esôfago/diagnóstico por imagem , Esôfago/patologia , Esôfago/fisiopatologia , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/prevenção & controle , Manometria , Radiografia , Testes de Função RespiratóriaRESUMO
Mycophenolate mofetil (MMF) significantly reduces proteinuria in experimental model of human membranous nephropathy (Heymann nephritis). Twenty consecutive SLE patients with persistent isolated severe proteinuria and/or proteinuric flare were studied for 18 months of MMF therapy. All of them presented stable renal function and 12 had biopsy proven membranous glomerulonephritis (WHO class V). The starting daily dose for MMF was 1.5 g to a maximum of 3 g. Patients were divided into: partial response, >or=50% decrease of baseline proteinuria; complete response, normal proteinuria levels (less than 0.3 g/24 h); flare, increase of at least 50% of the mean baseline proteinuria. All 20 SLE patients (100%) presented a 50% reduction of baseline proteinuria which was achieved in 8.2+/-3.3 months of MMF therapy, at a mean daily dose of 2.3+/-0.5 g. A significant decrease in 24-h protein excretion was observed compared to entry (3.47+/-1.26 vs. 1.33+/-0.67 g, P<0.0001) as well as a correspondent increase of serum albumin (3.2+/-0.4 vs. 3.7+/-0.4 mg/dl, P=0.02) and reduction of prednisone dose (33.7+/-20.0 to 18.6+/-14.1 mg/day, P=0.01). Complete response was observed in 11 SLE patients (55%) in 12.2+/-3.0 months of therapy with a significant decrease in proteinuria (P<0.0001), prednisone dose (P<0.0001) and an increase of serum albumin (P=0.003). Interestingly, initial proteinuria or serum albumin levels did not identify patients with complete response and those with partial response at the end of the study (P=0.543 and 0.657, respectively). Our pilot prospective study suggests that MMF appears to be effective in reducing severe persistent proteinuria in lupus glomerulonephritis, even in patients unresponsive to other immunosuppressive treatments.