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1.
BMJ Open Respir Res ; 8(1)2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34799353

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The 'indeterminate for usual interstitial pneumonia' (iUIP) CT pattern, defined in the 2018 IPF guidelines, could be a precursor to IPF but there is limited data on how patients with iUIP progress over time. OBJECTIVE: To evaluate the radiological progression of iUIP and explore factors linked to progression to IPF. METHODS: We performed a retrospective analysis of a lung fibrosis clinic cohort (n=230) seen between 2013 and 2017. Cases with iUIP were identified; first ever CTs for each patient found and categorised as 'non-progressor' or 'progressors' (the latter defined as increase in extent of disease or to 'definite' or 'probable' UIP CT pattern) during their follow-up. Lung function trends, haematological data and patient demographics were examined to explore disease evolution and potential contribution to progression. RESULTS: 48 cases with iUIP CT pattern were identified. Of these, 32 had follow-up CT scans, of which 23 demonstrated progression. 17 patients in this cohort were diagnosed with IPF over a mean (SD) period of 3.9 (±1.9) years. Monocyte (HR: 23, 95% CI: 1.6 to 340, p=0.03) and neutrophil levels (HR: 1.8, 95% CI: 1.3 to 2.3, p<0.001), obtained around the time of initial CT, were associated with progression to IPF using Cox proportional hazard modelling. CONCLUSION: 53% of our evaluable patients with iUIP progressed to IPF over a mean of 4 years. Monocyte and neutrophil levels at initial CT were significantly associated with progression in disease. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.

2.
Arthritis Res Ther ; 23(1): 234, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488870

RESUMO

BACKGROUND: The TßRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFß signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype. METHODS: PPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored. RESULTS: Gene expression data were consistent with the downregulation of the PPAR pathway in the TßRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure. CONCLUSIONS: In the TßRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications.


Assuntos
Fibrose Pulmonar , Escleroderma Sistêmico , Animais , Benzotiazóis , Camundongos , Camundongos Transgênicos , PPAR gama , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Transdução de Sinais , Sulfonamidas , Fator de Crescimento Transformador beta
4.
Respirology ; 26(5): 461-468, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33336433

RESUMO

BACKGROUND AND OBJECTIVE: The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. METHODS: Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. RESULTS: In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. CONCLUSION: Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.


Assuntos
Antígenos de Neoplasias/imunologia , Queratina-19/imunologia , Doenças Pulmonares Intersticiais , Pulmão/fisiologia , Escleroderma Sistêmico , Antígenos de Neoplasias/fisiologia , Biomarcadores , Progressão da Doença , Humanos , Queratina-19/fisiologia , Doenças Pulmonares Intersticiais/etiologia , Estudos Prospectivos , Estudos Retrospectivos , Escleroderma Sistêmico/complicações
5.
Am J Respir Crit Care Med ; 202(12): 1656-1665, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33007173

RESUMO

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.


Assuntos
COVID-19/epidemiologia , Hospitalização/estatística & dados numéricos , Doenças Pulmonares Intersticiais/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2 , Tomografia Computadorizada por Raios X
6.
BMJ Open Respir Res ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32928787

RESUMO

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Infecções por Coronavirus/terapia , Oxigenoterapia/métodos , Posicionamento do Paciente/métodos , Pneumonia Viral/terapia , Decúbito Ventral , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/métodos , Razão de Chances , Pandemias , Pneumonia Viral/mortalidade , Estudos Retrospectivos , SARS-CoV-2 , Resultado do Tratamento , Reino Unido , Vigília
7.
BMJ Open Respir Res ; 7(1)2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32527873

RESUMO

INTRODUCTION: There is currently no readily accessible measure to specifically quantify the amount of fibrosis in idiopathic pulmonary fibrosis (IPF). Such a measure could isolate contribution of fibrosis from other comorbidities to lung function abnormality and deterioration of disease, and potentially help determine if there has been response to antifibrotic treatment. METHODS: In a pilot study of 39 IPF patients, we used a CT-based visual scoring method to examine the correlation between the sum of all fibrotic features (all traction bronchiectasis, ground glass with traction bronchiectasis, honeycombing and reticulation; referred to as Total Fibrosis Score, TFS) or the individual fibrotic features, with lung function, Composite Physiologic Index (CPI) and time to death in the 5 years following CT measurement. RESULTS: TFS measurements were highly reproducible (r=0.982; p<0.001) and correlated significantly with TLCO, FVC and CPI. Traction bronchiectasis score was superior to others in its correlation to lung function and CPI, and as good as TFS. TFS and traction bronchiectasis score were also the best correlates (individually) to time to death (r=0.60 for both, and p=0.002 and p=0.004, respectively). CONCLUSION: We suggest that TFS and our 6-slices method of quantifying traction bronchiectasis on CT scans could be readily accessible and simple methods of quantifying lung fibrosis in IPF. These scores could assist in determining if clinical deterioration is due to worsening fibrosis, for correlation of research findings to amount of lung fibrosis, and to stratify patients for established drug treatment and clinical trials. Our findings also provide a basis for larger studies to validate these findings and determine if the scores could measure change in fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Análise de Regressão , Índice de Gravidade de Doença , Fatores de Tempo , Tomografia Computadorizada por Raios X
9.
Arthritis Rheumatol ; 69(8): 1670-1678, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28426895

RESUMO

OBJECTIVE: To determine the prognostic value of pulmonary function test (PFT) trends at 1 and 2 years in interstitial lung disease (ILD) associated with systemic sclerosis (SSc). METHODS: The prognostic significance of PFT trends at 1 year (n = 162) and 2 years (n = 140) was examined against 15-year survival in patients with SSc-associated ILD. PFT trends, expressed as continuous change and as categorical change in separate analyses, were examined against mortality in univariate and multivariate models. SSc-associated ILD was defined at presentation as either limited lung fibrosis or extensive lung fibrosis, using the United Kingdom Raynaud's and Scleroderma Association severity staging system. RESULTS: One-year PFT trends were predictive of mortality only in patients with extensive lung fibrosis: categorical change in the forced vital capacity (FVC), alone or in combination with categorical change in the diffusing capacity for carbon monoxide (DLco), had greater prognostic significance than continuous change in the FVC or trends in other PFT variables. Taking into account both prognostic value and sensitivity to change, the optimal definition of progression for trial purposes was an FVC and DLco composite end point, consisting of either an FVC decline from baseline of ≥10% or an FVC decline of 5-9% in association with a DLco decline of ≥15%. At 2 years, gas transfer trends had the greatest prognostic significance, in the whole cohort and in those with limited lung fibrosis. However, in patients with extensive lung fibrosis, the above-defined FVC and DLco composite end point was the strongest prognostic determinant. Larger changes in the FVC:DLco ratio than in the carbon monoxide transfer coefficient were required to achieve prognostic significance. CONCLUSION: Based on linkages to long-term outcomes, these findings provide support for use of routine spirometry and gas transfer monitoring in patients with SSc-associated ILD, with further evaluation of a composite FVC and DLco end point warranted for trial purposes.


Assuntos
Doenças Pulmonares Intersticiais/fisiopatologia , Pulmão/fisiopatologia , Fibrose Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Progressão da Doença , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Capacidade de Difusão Pulmonar , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/mortalidade , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/mortalidade , Índice de Gravidade de Doença , Reino Unido , Capacidade Vital
10.
J Allergy Clin Immunol Pract ; 5(4): 938-945, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28351785

RESUMO

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).


Assuntos
Imunodeficiência de Variável Comum , Granuloma , Doenças Pulmonares Intersticiais , Instituições de Caridade , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/diagnóstico por imagem , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/patologia , Consenso , Granuloma/diagnóstico , Granuloma/diagnóstico por imagem , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Sociedades Médicas , Reino Unido
11.
Clin Med (Lond) ; 16(1): 42-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26833513

RESUMO

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive accumulation of scar tissue in the lung and is associated with a median life expectancy of 2-4 years. Until recently, treatment options were limited, focusing on ineffective anti-inflammatory therapy, palliation, transplant or trial recruitment. Significant recent advances in the field have led to two novel anti-fibrotic agents, pirfenidone and nintedanib, which have been shown to significantly slow disease progression in IPF. This article outlines the approach to management of IPF, the role of specialist centres and specialist interstitial lung disease multidisciplinary review, and explores both the trial evidence and practical considerations in the use of these anti-fibrotic agents.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Anti-Inflamatórios/uso terapêutico , Humanos , Fibrose Pulmonar Idiopática/terapia , Indóis/uso terapêutico , Piridonas/uso terapêutico
12.
Adv Ther ; 32(10): 929-43, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26498943

RESUMO

INTRODUCTION: There is a lack of agreed and established guidelines for the treatment of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This reflects, in part, the limited evidence-base underpinning the management of AE-IPF. In the absence of high-quality evidence, the aim of this research was to develop a clinician-led consensus statement for the definition, diagnosis and treatment of AE-IPF. METHODS: A literature review was conducted to obtain published material on the definition and treatment of AE-IPF. The results of this review were circulated to an online panel of clinicians for review. Statements were then shared with ten expert respiratory clinicians who regularly treat patients with IPF. A Delphi technique was then used to develop a consensus statement for the definition, diagnosis and treatment of AE-IPF. During the first round of review, clinicians rated the clarity of each statement, the extent to which the statement should be included and provided comments. In two subsequent rounds of review, clinicians were provided with the group median inclusion rating for each statement, and any revised wording of statements to aid clarity. Clinicians were asked to repeat the clarity and inclusion ratings for the revised statements. RESULTS: The literature review, online panel discussion, and face-to-face meeting generated 65 statements covering the definition, diagnosis, and management of AE-IPF. Following three rounds of blind review, 90% of clinicians agreed 39 final statements. These final statements included a definition of AE-IPF, approach to diagnosis, and treatment options, specifically: supportive measures, use of anti-microbials, immunosuppressants, anti-coagulants, anti-fibrotic therapy, escalation, transplant management, and long-term management including discharge planning. CONCLUSION: This clinician-led consensus statement establishes the 'best practice' for the management and treatment of AE-IPF based on current knowledge, evidence, and available treatments.


Assuntos
Consenso , Técnica Delfos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/terapia , Guias de Prática Clínica como Assunto , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Alta do Paciente
14.
Am J Respir Crit Care Med ; 183(2): 249-61, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20709822

RESUMO

RATIONALE: Fibrotic response to lung injury depends on development of a fibrogenic population of myofibroblasts. The importance of resident interstitial fibroblasts and role of transforming growth factor ß (TGFß) in this process is unclear. OBJECTIVES: To define the importance of TGFß signaling in resident lung fibroblasts in the development of experimental pulmonary fibrosis. METHODS: A compound genetic strategy in which mice homozygous for a floxed high-affinity type II TGFß receptor (TßRII) allele were crossed with a transgenic strain harboring a fibroblast-specific transgene encoding ligand-dependent Cre-recombinase was used. TßRII was deleted by postnatal administration of tamoxifen over 5 days to compound mutant mice with appropriate littermate controls. Illumina microarray gene profiling and quantitative reverse transcriptase-polymerase chain reaction were used to confirm anergy to TGFß in explanted lung fibroblasts. Bleomycin lung injury was used to induce lung fibrosis, which was analyzed by histology and biochemical methods. Immunofluorescence was used to define cell populations after lung injury. MEASUREMENTS AND MAIN RESULTS: There was significant attenuation of fibrosis in mice after deletion of TßRII in resident fibroblasts. At 7 days after injury the number of fibrocytes and myofibroblasts was substantially reduced. Potential regulators of fibrosis were suggested by gene expression profiles that identified key candidate profibrotic genes, including connective tissue growth factor and endothelin-1 expressed by wild-type but not mutant lung fibroblasts. CONCLUSIONS: Intact TGFß signaling in resident pulmonary fibroblasts is essential for pulmonary fibrosis to develop. Our data support a key regulatory role of these cells in determining fibrocyte recruitment and myofibroblast differentiation.


Assuntos
Fibroblastos/metabolismo , /metabolismo , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Deleção de Sequência/genética , Animais , Bleomicina , Western Blotting , Linhagem da Célula , Células Cultivadas , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise Serial de Proteínas/métodos , Receptor do Fator de Crescimento Transformador beta Tipo II , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transdução de Sinais/genética , Tamoxifeno , Transcrição Genética/genética
15.
Arthritis Rheum ; 60(7): 2142-55, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19565505

RESUMO

OBJECTIVE: Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor beta (TGFbeta) and is a mediator of some profibrotic effects of TGFbeta in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I alpha2) in this mouse model and in human pulmonary fibroblasts. METHODS: Transgenic mice that were carrying luciferase and beta-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts. RESULTS: In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by approximately 25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycin-treated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling. CONCLUSION: Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation of Col1a2. Blocking strategies revealed the signaling mechanisms involved. These findings show CTGF to be a rational target for therapy in fibrotic diseases such as SSc.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fibrose Pulmonar/metabolismo , Transcrição Genética/fisiologia , Animais , Sequência de Bases , Bleomicina/efeitos adversos , Células Cultivadas , Colágeno/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/antagonistas & inibidores , Fator de Crescimento do Tecido Conjuntivo/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Transcrição Genética/efeitos dos fármacos
16.
J Invest Dermatol ; 129(1): 194-204, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18563179

RESUMO

Previous attempts to delete type II TGFbeta receptor (TbetaRII) in fibroblasts have precluded examination of adult mice due to early mortality. We have selectively deleted TbetaRII postnatally in differentiated connective tissue fibroblasts using an inducible Cre-Lox strategy. Tamoxifen-dependent Cre recombinase linked to a fibroblast-specific regulatory sequence from the proalpha2(I)collagen gene permitted deletion of floxed TbetaRII alleles. After postnatal deletion of TbetaRII in fibroblasts, healing of excisional skin wounds in adults showed markedly attenuated dermal scar formation, defective wound contraction and enhanced epidermal proliferation. These findings support a pivotal role for transforming growth factor beta (TGFbeta) signalling in fibroblasts in regulating normal skin wound healing. Explanted dermal fibroblasts from TbetaRII-null-fib mice showed impaired migration and did not generate normal contractile biomechanical forces in fixed collagen gels nor develop alpha-smooth muscle antigen-rich stress fibers in response to TGFbeta1. Surprisingly, some TGFbeta-regulated proteins, including connective tissue growth factor (CTGF), were basally upregulated in TbetaRII-null fibroblasts and this was dependent on extracellular signal-regulated kinase 1/2 activity in these cells. This suggests that other intracellular pathways regulating CTGF expression may partially compensate for disruption of TGFbeta signalling in fibroblasts. Together, our data confirm that expression of TbetaRII in differentiated dermal fibroblasts is essential for normal wound healing and demonstrate a critical role in the development and function of myofibroblasts.


Assuntos
Fibroblastos/metabolismo , /metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Pele/patologia , Alelos , Animais , Fenômenos Biomecânicos , Linhagem da Célula , Citoesqueleto , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Deleção de Genes , Camundongos , Músculos/citologia , Receptor do Fator de Crescimento Transformador beta Tipo II , Transdução de Sinais , Cicatrização
17.
Arthritis Rheum ; 58(4): 1175-88, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18383385

RESUMO

OBJECTIVE: To explore increased susceptibility to fibrosis following experimental injury to alveolar epithelial cells (AECs) in a novel transgenic mouse model of scleroderma with fibroblast-specific perturbation of transforming growth factor beta (TGFbeta) signaling (TbetaRIIDeltak-fib mice). METHODS: Wild-type (WT) and transgenic mice were injured with intratracheally administered saline or bleomycin, and the lungs were harvested for biochemical, histologic, and electron microscopic analysis. RESULTS: Electron microscopy revealed AEC abnormalities in the lungs of untreated transgenic mice and bleomycin-treated WT mice; the lungs of transgenic mice treated with bleomycin showed severe epithelial damage. Compared with lungs from bleomycin-treated WT mice, lungs from bleomycin-treated transgenic mice demonstrated increased fibroproliferation, myofibroblast persistence, and impaired hyperplasia and increased apoptosis of type II AECs. The lungs from saline-treated transgenic mice and those from bleomycin-treated WT mice had phenotypic similarities, suggesting enhanced susceptibility to minor epithelial injury in the transgenic strain. The level of collagen was increased in the lungs from transgenic mice compared with that in the lungs from WT mice after treatment with either bleomycin or saline. Persistent fibrosis in bleomycin-treated transgenic mice was independent of ongoing neutrophil inflammation but was associated with impaired alveolar epithelial repair. CONCLUSION: These results suggest that in the context of fibroblast-specific perturbation of TGFbeta signaling, even minor epithelial injury induces significant fibrosis. The model supports a central role for TGFbeta in determining fibrosis and demonstrates that lung fibroblasts may regulate the response of AECs to injury. Our findings provide insight into likely pathogenic mechanisms in scleroderma-associated pulmonary fibrosis.


Assuntos
Fibroblastos/metabolismo , Fibrose Pulmonar/complicações , Fibrose Pulmonar/fisiopatologia , Escleroderma Sistêmico , Fator de Crescimento Transformador beta/metabolismo , Animais , Bleomicina/administração & dosagem , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais , Irritantes/administração & dosagem , Camundongos , Camundongos Transgênicos , Alvéolos Pulmonares/citologia , Fibrose Pulmonar/induzido quimicamente , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Transdução de Sinais , Cloreto de Sódio/administração & dosagem
18.
Arthritis Rheum ; 54(12): 3962-70, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17133610

RESUMO

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.


Assuntos
Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Prednisolona/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/fisiopatologia , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Resultado do Tratamento
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