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1.
Curr Rheumatol Rep ; 22(8): 37, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32562128

RESUMO

PURPOSE OF REVIEW: The etiology of systemic sclerosis (SSc), which is a rare immune-mediated inflammatory disease characterized by vascular damage and fibrosis, is still unknown. However, different intrinsic (genetics) and extrinsic (environmental) factors play a part in the progression of the disease. This review focuses on the role of aging, mitochondrial dysfunction, and senescence in SSc. RECENT FINDINGS: Mitochondrial dysfunction and senescence have been linked to the age-related susceptibility to other interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF). SSc is not regarded as an age-related disease but does show a higher incidence of cardiac events, fibrosis, and mortality at older age. We provide an overview of the current status of the role of aging, mitochondrial dysfunction, and senescence in SSc. Further work is needed to validate some of these pathways in SSc and may allow for new therapeutic interventions focused on restoring mitochondrial homeostasis and the targeted removal of chronic-senescent cells.

2.
J Biol Chem ; 295(13): 4171-4180, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32071084

RESUMO

Systemic scleroderma (SSc) is an autoimmune disease that affects over 2.5 million people globally. SSc results in dysfunctional connective tissues with excessive profibrotic signaling, affecting skin, cardiovascular, and particularly lung tissue. Over three-quarters of individuals with SSc develop pulmonary fibrosis within 5 years, the main cause of SSc mortality. No approved medicines to manage lung SSc currently exist. Recent research suggests that profibrotic signaling by transforming growth factor ß (TGF-ß) is directly tied to SSc. Previous studies have also shown that ubiquitin E3 ligases potently control TGF-ß signaling through targeted degradation of key regulatory proteins; however, the roles of these ligases in SSc-TGF-ß signaling remain unclear. Here we utilized primary SSc patient lung cells for high-throughput screening of TGF-ß signaling via high-content imaging of nuclear translocation of the profibrotic transcription factor SMAD family member 2/3 (SMAD2/3). We screened an RNAi library targeting ubiquitin E3 ligases and observed that knockdown of the E3 ligase Kelch-like protein 42 (KLHL42) impairs TGF-ß-dependent profibrotic signaling. KLHL42 knockdown reduced fibrotic tissue production and decreased TGF-ß-mediated SMAD activation. Using unbiased ubiquitin proteomics, we identified phosphatase 2 regulatory subunit B'ϵ (PPP2R5ϵ) as a KLHL42 substrate. Mechanistic experiments validated ubiquitin-mediated control of PPP2R5ϵ stability through KLHL42. PPP2R5ϵ knockdown exacerbated TGF-ß-mediated profibrotic signaling, indicating a role of PPP2R5ϵ in SSc. Our findings indicate that the KLHL42-PPP2R5ϵ axis controls profibrotic signaling in SSc lung fibroblasts. We propose that future studies could investigate whether chemical inhibition of KLHL42 may ameliorate profibrotic signaling in SSc.

3.
JCI Insight ; 4(19)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578312

RESUMO

Dysregulated proinflammatory cytokine release has been implicated in the pathogenesis of several life-threatening acute lung illnesses such as pneumonia, sepsis, and acute respiratory distress syndrome. Suppressors of cytokine signaling proteins, particularly SOCS2, have recently been described as antiinflammatory mediators. However, the regulation of SOCS2 protein has not been described. Here we describe a mechanism of SOCS2 regulation by the action of the ubiquitin E3 ligase KIAA0317. KIAA0317-mediated degradation of SOCS2 exacerbated inflammation in vitro, and depletion of KIAA0317 in vivo ameliorated pulmonary inflammation. KIAA0317-knockout mice exhibited resistance to LPS-induced pulmonary inflammation, while KIAA03017 reexpression mitigated this effect. We uncovered a small molecule inhibitor of KIAA0317 protein (BC-1365) that prevented SOCS2 degradation and attenuated LPS- and P. aeruginosa-induced lung inflammation in vivo. These studies show KIAA0317 to be a critical mediator of pulmonary inflammation through its degradation of SOCS2 and a potential candidate target for therapeutic inhibition.

4.
Ann Rheum Dis ; 78(10): 1379-1387, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405848

RESUMO

OBJECTIVES: Myofibroblasts are key effector cells in the extracellular matrix remodelling of systemic sclerosis-associated interstitial lung disease (SSc-ILD); however, the diversity of fibroblast populations present in the healthy and SSc-ILD lung is unknown and has prevented the specific study of the myofibroblast transcriptome. We sought to identify and define the transcriptomes of myofibroblasts and other mesenchymal cell populations in human healthy and SSc-ILD lungs to understand how alterations in fibroblast phenotypes lead to SSc-ILD fibrosis. METHODS: We performed droplet-based, single-cell RNA-sequencing with integrated canonical correlation analysis of 13 explanted lung tissue specimens (56 196 cells) from four healthy control and four patients with SSc-ILD, with findings confirmed by cellular indexing of transcriptomes and epitopes by sequencing in additional samples. RESULTS: Examination of gene expression in mesenchymal cells identified two major, SPINT2hi and MFAP5hi, and one minor, WIF1hi, fibroblast populations in the healthy control lung. Combined analysis of control and SSc-ILD mesenchymal cells identified SPINT2hi, MFAP5hi, few WIF1hi fibroblasts and a new large myofibroblast population with evidence of actively proliferating myofibroblasts. We compared differential gene expression between all SSc-ILD and control mesenchymal cell populations, as well as among the fibroblast subpopulations, showing that myofibroblasts undergo the greatest phenotypic changes in SSc-ILD and strongly upregulate expression of collagens and other profibrotic genes. CONCLUSIONS: Our results demonstrate previously unrecognised fibroblast heterogeneity in SSc-ILD and healthy lungs, and define multimodal transcriptome-phenotypes associated with these populations. Our data indicate that myofibroblast differentiation and proliferation are key pathological mechanisms driving fibrosis in SSc-ILD.


Assuntos
Fibroblastos/metabolismo , Heterogeneidade Genética , Doenças Pulmonares Intersticiais/genética , Miofibroblastos/metabolismo , Escleroderma Sistêmico/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Estudos de Casos e Controles , Proliferação de Células/genética , Colágeno/genética , Proteínas Contráteis/metabolismo , Epitopos , Feminino , Perfilação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/citologia , Masculino , Glicoproteínas de Membrana/metabolismo , Mesoderma/citologia , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/genética , Escleroderma Sistêmico/complicações , Análise de Célula Única , Transcriptoma
5.
Eur Respir J ; 54(2)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31221805

RESUMO

A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis.We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs.IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs.Co-localisation and causal modelling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.

7.
Arch Pathol Lab Med ; 141(7): 960-969, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28467213

RESUMO

CONTEXT: - Patients with idiopathic interstitial pneumonia may display evidence of autoimmunity without meeting criteria for a defined connective tissue disease. A recent European Respiratory Society/American Thoracic Society statement proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), which includes findings from the clinical, serologic, and morphologic domains. OBJECTIVES: - To investigate the importance of histopathologic criteria within the morphologic domain and to report our methodology for identifying these features. DESIGN: - Patients with idiopathic interstitial pneumonia at the University of Chicago who underwent surgical lung biopsy or lung transplantation were assessed for IPAF histopathologic features, using the initial pathology interpretation in the electronic records. A focused rereview of available slides by a pulmonary pathologist was then performed for patients who failed to meet IPAF criteria on initial pathology assessment. RESULTS: - Of 422 patients with idiopathic interstitial pneumonia, 176 (41.7%) underwent surgical lung biopsy or lung transplant. Forty-six of those 176 patients (26.1%) met IPAF criteria by initial pathology interpretation and a positive clinical or serologic feature. Of the remaining 130 patients, 73 (56.2%) met either the clinical or serologic domains without meeting the morphologic domain, whereas 36 (27.7%) had slides available for pathology rereview. This rereview demonstrated nonspecific interstitial pneumonia in 8 of 36 patients (22.2%) and lymphoplasmacytic infiltrates in 6 of 36 patients (16.7%), resulting in an additional 7 of 36 patients (19.4%) with idiopathic interstitial pneumonia that met the IPAF criteria. In IPAF, pulmonary vasculopathy was the most prevalent finding (45 of 84; 53.6%) and predicted increased mortality (hazard ratio, 2.5; P = .04). CONCLUSIONS: - Using a methodological approach to identifying IPAF pathology, we demonstrate a significant increase in the number of patients meeting IPAF criteria because of focused pathologic review and highlight the prognostic value of the IPAF pathologic findings.


Assuntos
Autoimunidade , Pneumonias Intersticiais Idiopáticas/diagnóstico , Patologia Clínica/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Respir Med ; 121: 117-122, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27888985

RESUMO

BACKGROUND: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. METHODS: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. RESULTS: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. CONCLUSIONS: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.


Assuntos
Azatioprina/uso terapêutico , Doenças do Tecido Conjuntivo/complicações , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Adulto , Idoso , Azatioprina/efeitos adversos , Doenças do Tecido Conjuntivo/fisiopatologia , Estudos Cross-Over , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Capacidade de Difusão Pulmonar/efeitos dos fármacos , Sistema de Registros , Estudos Retrospectivos , Capacidade Vital/efeitos dos fármacos
9.
Eur Respir J ; 47(6): 1767-75, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27103387

RESUMO

Patients with interstitial lung disease (ILD) may have features of connective tissue disease (CTD), but lack findings diagnostic of a specific CTD. A recent European Respiratory Society/American Thoracic Society research statement proposed criteria for patients with interstitial pneumonia with autoimmune features (IPAF).We applied IPAF criteria to patients with idiopathic interstitial pneumonia and undifferentiated CTD-ILD (UCTD). We then characterised the clinical, serological and morphological features of the IPAF cohort, compared outcomes to other ILD cohorts and validated individual IPAF domains using survival as an endpoint.Of 422 patients, 144 met IPAF criteria. Mean age was 63.2 years with a slight female predominance. IPAF cohort survival was marginally better than patients with idiopathic pulmonary fibrosis, but worse than CTD-ILD. A non-usual interstitial pneumonia pattern was associated with improved survival, as was presence of the clinical domain. A modified IPAF cohort of those meeting the clinical domain and a radiographic or histological feature within the morphological domain displayed survival similar to those with CTD-ILD.IPAF is common among patients with idiopathic interstitial pneumonia and UCTD. Specific IPAF features can identify subgroups with differential survival. Further research is needed to replicate these findings and determine whether patients meeting IPAF criteria benefit from immunosuppressive therapy.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/imunologia , Idoso , Biópsia , Estudos de Coortes , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/imunologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
10.
Am J Respir Crit Care Med ; 192(12): 1475-82, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26331942

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. OBJECTIVES: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. METHODS: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥ 10% in FVC. MEASUREMENTS AND MAIN RESULTS: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. CONCLUSIONS: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.


Assuntos
Acetilcisteína/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mucina-5B/genética , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Fibrose Pulmonar Idiopática/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Mucina-5B/imunologia , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Risco
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