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1.
Aging (Albany NY) ; 13(5): 6273-6288, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33647885

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. The current coronavirus disease 2019 (COVID-19) shares some similarities with IPF. SARS-CoV-2 related genes have been reported to be broadly regulated by N6-methyladenosine (m6A) RNA modification. Here, we identified the association between m6A methylation regulators, COVID-19 infection pathways, and immune responses in IPF. The characteristic gene expression networks and immune infiltration patterns of m6A-SARS-CoV-2 related genes in different tissues of IPF were revealed. We subsequently evaluated the influence of these related gene expression patterns and immune infiltration patterns on the prognosis/lung function of IPF patients. The IPF cohort was obtained from the Gene Expression Omnibus dataset. Pearson correlation analysis was performed to identify the correlations among genes or cells. The CIBERSORT algorithm was used to assess the infiltration of 22 types of immune cells. The least absolute shrinkage and selection operator (LASSO) and proportional hazards model (Cox model) were used to develop the prognosis prediction model. Our research is pivotal for further understanding of the cellular and genetic links between IPF and SARS-CoV-2 infection in the context of the COVID-19 pandemic, which may contribute to providing new ideas for prognosis assessment and treatment of both diseases.


Assuntos
Adenosina/análogos & derivados , Redes Reguladoras de Genes , Fibrose Pulmonar Idiopática/genética , Adenosina/genética , Adenosina/imunologia , Algoritmos , /imunologia , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/imunologia , Imunidade , Imunidade Celular , Prognóstico , RNA/genética , RNA/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , /isolamento & purificação
2.
EBioMedicine ; 65: 103277, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33714028

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. METHODS: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls). FINDINGS: We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) . INTERPRETATION: The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. FUNDING: Novo Nordisk Foundation and Oak Foundation.


Assuntos
/patologia , Predisposição Genética para Doença/genética , Fibrose Pulmonar Idiopática/patologia , /genética , Estudo de Associação Genômica Ampla , Humanos , Fibrose Pulmonar Idiopática/genética , Pulmão/patologia , Mucina-5B/genética , Polimorfismo de Nucleotídeo Único/genética , Risco , Índice de Gravidade de Doença
3.
Nat Commun ; 12(1): 1072, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594057

RESUMO

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.


Assuntos
Desmetilação do DNA , Nucleossomos/metabolismo , Iniciação da Transcrição Genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Cromatina/química , Cromatina/metabolismo , Células HEK293 , Proteína HMGA2/metabolismo , Histonas/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Camundongos , Fosforilação , Fosfosserina/metabolismo , RNA Polimerase II/metabolismo , Sítio de Iniciação de Transcrição , Ativação Transcricional/genética , Fator de Crescimento Transformador beta1/metabolismo
4.
Adv Protein Chem Struct Biol ; 123: 241-273, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33485486

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a rare yet crucial persistent lung disorder that actuates scarring of lung tissues, which makes breathing difficult. Smoking, environmental pollution, and certain viral infections could initiate lung scarring. However, the molecular mechanism involved in IPF remains elusive. To develop an efficient therapeutic arsenal against IPF, it is vital to understand the pathology and deviations in biochemical pathways that lead to disorder. In this study, we availed network analysis and other computational pipelines to delineate the prominent membrane proteins as diagnostic biomarkers and therapeutic targets for IPF. This study yielded a significant role of glycosaminoglycan binding, endothelin, and GABA-B receptor signaling pathway in IPF pathogenesis. Furthermore, ADCY8, CRH, FGB, GPR17, MCHR1, NMUR1, and SAA1 genes were found to be immensely involved with IPF, and the enrichment pathway analysis suggests that most of the pathways were corresponding to membrane transport and signal transduction functionalities. This analysis could help in better understanding the molecular mechanism behind IPF to develop an efficient therapeutic target or biomarkers for IPF.


Assuntos
Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Regulação da Expressão Gênica , Fibrose Pulmonar Idiopática , Proteínas de Membrana , Transdução de Sinais/genética , Transcriptoma , Biomarcadores/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430153

RESUMO

Lung diseases (LD) are one of the most common causes of death worldwide. Although it is known that chronic airway inflammation and excessive tissue repair are processes associated with LD such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF), their specific pathways remain unclear. Extracellular vesicles (EVs) are heterogeneous nanoscale membrane vesicles with an important role in cell-to-cell communication. EVs are present in general biofluids as plasma or urine but also in secretions of the airway as bronchoalveolar lavage fluid (BALF), induced sputum (IS), nasal lavage (NL) or pharyngeal lavage. Alterations of airway EV cargo could be crucial for understanding LD. Airway EVs have shown a role in the pathogenesis of some LD such as eosinophil increase in asthma, the promotion of lung cancer in vitro models in COPD and as biomarkers to distinguishing IPF in patients with diffuse lung diseases. In addition, they also have a promising future as therapeutics for LD. In this review, we focus on the importance of airway secretions in LD, the pivotal role of EVs from those secretions on their pathophysiology and their potential for biomarker discovery.


Assuntos
Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Pneumopatias/metabolismo , Pulmão/metabolismo , Asma/genética , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/química , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Pneumopatias/genética , Lavagem Nasal , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Escarro/química
7.
Mol Med ; 26(1): 95, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054759

RESUMO

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Assuntos
Infecções por Coronavirus/imunologia , Epigênese Genética/imunologia , Fibrose Pulmonar Idiopática/imunologia , Mecanotransdução Celular/imunologia , Pneumonia Viral/imunologia , Embolia Pulmonar/imunologia , Insuficiência Respiratória/imunologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Fenômenos Biomecânicos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mecanotransdução Celular/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/genética , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia , Estresse Mecânico
8.
Adv Exp Med Biol ; 1255: 73-81, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949391

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic complex lung disease with no specific treatment and poor prognosis, characterized by the pulmonary progressive fibrosis and dysfunctions that lead to respiratory failure. Several factors may impact the progress of IPF, including age, cigarette smoking, and dusts, of which genetic and epigenetic factors mainly contribute to lung tissue fibrosis. DNA methylation is one of epigenetic processes that occur in many diseases and regulate chromosomal and extrachromosomal DNA functions in response to environmental exposures. The methylation plays pivotal roles in regulation of gene expression to facilitate the formation of fibroblastic foci and lung fibrosis. This chapter will describe alterations and effects of the DNA methylation on gene expression, the potential application of DNA methylation as a biomarker, and significance as therapeutic targets. Those understanding will provide us new insight into the treatment and prognosis of IPF.


Assuntos
Metilação de DNA , Fibrose Pulmonar Idiopática/genética , Epigênese Genética , Epigenômica , Expressão Gênica , Humanos
9.
Medicine (Baltimore) ; 99(36): e22099, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899090

RESUMO

Idiopathic pulmonary fibrosis is a chronic and irreversible respiratory disease with a high incidence worldwide and no specific treatment. Currently, the etiology and pathogenesis of this disease remain largely unknown. In main purpose of this study, bioinformatics analysis was used to uncover key genes and pathways related to idiopathic pulmonary fibrosis (IPF). Gene expression profiles of GSE2052 and GSE35145 were obtained. After combining the 2 chip groups; then, we normalized the data, eliminating batch difference. R software was used to process and to screen differentially expressed genes (DEGs) between the IPF and normal tissues. Then, functional enrichment analysis of these DEGs was carried out, and a protein-protein interaction network (PPI) was also constructed. A total of 276 DEGs (152 up and 134 down-regulated genes) were identified in the IPF lung samples. The PPI network was established with 227 nodes and 763 edges. The top 10 hub genes were CAM1, CDH1, CXCL12, JUN, CTGF, SERPINE1, CXCL1, EDN1, COL1A2, and SPARC. Analyzing the PPI network modules with close interaction, the 3 key modules in the whole PPI network were screened out. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched for the module containing DEGs contained the viral protein interaction with cytokine and the cytokine receptor, the TNF signaling pathway, and the chemokine signaling pathway. The identified key genes and pathways may play an important role in the occurrence and development of IPF, and may be expected to be biomarkers or therapeutic targets for the diagnosis of IPF.


Assuntos
Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Mapeamento de Interação de Proteínas
10.
PLoS One ; 15(9): e0237529, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941426

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. "Bronchiolization", characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1+ club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1+MUC5B+ club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1+SCGB3A2high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Transcriptoma , Bronquíolos/citologia , Bronquíolos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Pulmão/citologia , Mucosa Respiratória/citologia , Mucosa Respiratória/patologia , Secretoglobinas/genética , Análise de Célula Única , Uteroglobina/genética
12.
Am J Respir Crit Care Med ; 202(10): 1430-1444, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32602730

RESUMO

Rationale: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of subjects with CHP have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF).Objectives: To determine the common and unique molecular features of CHP and IPF.Methods: Transcriptome analysis of lung samples from CHP (n = 82), IPF (n = 103), and unaffected controls (n = 103) was conducted. Differential gene expression was determined adjusting for sex, race, age, and smoking history and using false discovery rate to control for multiple comparisons.Measurements and Main Results: When compared with controls, we identified 413 upregulated and 317 downregulated genes in CHP and 861 upregulated and 322 downregulated genes in IPF. Concordantly upregulated or downregulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP (differentially expressed in CHP when compared with control and not differentially expressed in IPF) were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene coexpression network analysis, we found that among subjects with CHP, genes involved in adaptive immunity or epithelial cell development were associated with improved or reduced lung function, respectively, and that MUC5B expression was associated with epithelial cell development. MUC5B expression was also associated with lung fibrosis and honeycombing.Conclusions: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP.


Assuntos
Alveolite Alérgica Extrínseca/genética , Alveolite Alérgica Extrínseca/imunologia , Perfilação da Expressão Gênica , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alveolite Alérgica Extrínseca/fisiopatologia , Feminino , Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade
13.
Am J Respir Crit Care Med ; 202(9): 1225-1236, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32551799

RESUMO

Rationale: Genetic association studies have identified rs2076295 in association with idiopathic pulmonary fibrosis (IPF). We hypothesized that rs2076295 is the functional variant regulating DSP (desmoplakin) expression in human bronchial epithelial cells, and DSP regulates extracellular matrix-related gene expression and cell migration, which is relevant to IPF development.Objectives: To determine whether rs2076295 regulates DSP expression and the function of DSP in airway epithelial cells.Methods: Using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 editing (including regional deletion, indel, CRISPR interference, and single-base editing), we modified rs2076295 and measured DSP expression in edited 16HBE14o- and primary airway epithelial cells. Cellular integrity, migration, and genome-wide gene expression changes were examined in 16HBE14o- single colonies with DSP knockout. The expression of DSP and its relevant matrix genes was measured by quantitative PCR and also analyzed in single-cell RNA-sequencing data from control and IPF lungs.Measurements and Main Results: DSP is expressed predominantly in bronchial and alveolar epithelial cells, with reduced expression in alveolar epithelial cells in IPF lungs. The deletion of the DNA region-spanning rs2076295 led to reduced expression of DSP, and the edited rs2076295GG 16HBE14o- line has lower expression of DSP than the rs2076295TT lines. Knockout of DSP in 16HBE14o- cells decreased transepithelial resistance but increased cell migration, with increased expression of extracellular matrix-related genes, including MMP7 and MMP9. Silencing of MMP7 and MMP9 abolished increased migration in DSP-knockout cells.Conclusions: rs2076295 regulates DSP expression in human airway epithelial cells. The loss of DSP enhances extracellular matrix-related gene expression and promotes cell migration, which may contribute to the pathogenesis of IPF.


Assuntos
Desmoplaquinas/genética , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/fisiopatologia , Células Epiteliais Alveolares , Células Epiteliais , Humanos
14.
Respir Investig ; 58(5): 320-335, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32487481

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.


Assuntos
Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/terapia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Feminino , Fibrose , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/patologia , Pulmão/microbiologia , Pulmão/patologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Prognóstico , Piridonas/uso terapêutico , Telômero
15.
Cancer Sci ; 111(7): 2482-2487, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32426915

RESUMO

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF-associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF-associated non-small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next-generation sequencing with a panel that targets 161 cancer-related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS-RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF-associated lung cancer, and the RAS-RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF-associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Fibrose Pulmonar Idiopática/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Biomarcadores , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência de DNA
16.
Nucleic Acids Res ; 48(W1): W597-W602, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32392295

RESUMO

High-throughput sequencing and the availability of large online data repositories (e.g. The Cancer Genome Atlas and Trans-Omics for Precision Medicine) have the potential to revolutionize systems biology by enabling researchers to study interactions between data from different modalities (i.e. genetic, genomic, clinical, behavioral, etc.). Currently, data mining and statistical approaches are confined to identifying correlates in these datasets, but researchers are often interested in identifying cause-and-effect relationships. Causal discovery methods were developed to infer such cause-and-effect relationships from observational data. Though these algorithms have had demonstrated successes in several biomedical applications, they are difficult to use for non-experts. So, there is a need for web-based tools to make causal discovery methods accessible. Here, we present CausalMGM (http://causalmgm.org/), the first web-based causal discovery tool that enables researchers to find cause-and-effect relationships from observational data. Web-based CausalMGM consists of three data analysis tools: (i) feature selection and clustering; (ii) automated identification of cause-and-effect relationships via a graphical model; and (iii) interactive visualization of the learned causal (directed) graph. We demonstrate how CausalMGM enables an end-to-end exploratory analysis of biomedical datasets, giving researchers a clearer picture of its capabilities.


Assuntos
Software , Análise por Conglomerados , Gráficos por Computador , Conjuntos de Dados como Assunto , Diagnóstico Diferencial , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Internet , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , RNA-Seq
17.
Nat Commun ; 11(1): 2012, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332792

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFß signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.


Assuntos
Células Epiteliais/patologia , Fibrose Pulmonar Idiopática/genética , Pulmão/patologia , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Adulto , Idoso , Animais , Biópsia , Modelos Animais de Doenças , Canais Epiteliais de Sódio/metabolismo , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mucina-5B/metabolismo , Proteômica , Piridonas/administração & dosagem , Ubiquitinação
18.
BMC Med Genet ; 21(1): 71, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32252656

RESUMO

BACKGROUND: Herein, we collected currently published data to comprehensively evaluate the impact of the FCGR2A (Fc fragment of IgG receptor IIa) rs1801274 and MUC5B (mucin 5B, oligomeric mucus/gel-forming) rs35705950 variations on susceptibility to pneumonia diseases. METHODS: We retrieved case-control studies from three online databases and applied the statistical approach of meta-analysis for a series of pooling analyses. RESULTS: A total of fourteen case-control studies were included for FCGR2A rs1801274; while thirty-one case-control studies were included for MUC5B rs35705950. No significant difference between pneumonia cases and controls for FCGR2A rs1801274 was found. However, MUC5B rs35705950 was significantly associated with pneumonia susceptibility in the whole population under the genetic models of allelic T vs. G [OR (odds ratio) =3.78], carrier T vs. G (OR = 3.31), TT vs. GG (OR = 13.66), GT vs. GG (OR = 4.78), GT + TT vs. GG (OR = 5.05), and TT vs. GG + GT (OR = 6.47) (all P < 0.001, Bonferroni-adjusted P < 0.006; false discovery rate-adjusted P < 0.0010). Furthermore, we observed a similar positive result for subgroup analyses of "Caucasian", "Asian", "population-based control", and "idiopathic pulmonary fibrosis". CONCLUSIONS: MUC5B rs35705950, but not FCGR2A rs1801274, increases susceptibility to clinical pneumonia, especially to idiopathic pulmonary fibrosis, in both the Caucasian and Asian populations.


Assuntos
Mucina-5B/genética , Pneumonia/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/genética , Pneumonia/epidemiologia
19.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121297

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1ß and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA-miRNA-AIM2 inflammasome axis in the pathogenesis of IPF.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fibrose Pulmonar Idiopática/genética , Inflamassomos/metabolismo , MicroRNAs/metabolismo , Ribonuclease III/metabolismo , Animais , Humanos , MicroRNAs/genética , Modelos Biológicos
20.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L852-L863, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159970

RESUMO

Idiopathic pulmonary fibrosis (IPF) results in scarring of the lungs by excessive extracellular matrix (ECM) production. Resident fibroblasts are the major cell type involved in ECM deposition. The biochemical pathways that facilitate pathological fibroblast activation leading to aberrant ECM deposition are not fully understood. Tank binding protein kinase-1 (TBK1) is a kinase that regulates multiple signaling pathways and was recently identified as a candidate regulator of fibroblast activation in a large-scale small-interfering RNA (siRNA) screen. To determine the effect of TBK1 on fibroblast activation, TBK1 was inhibited pharmacologically (MRT-68601) and genetically (siRNA) in normal and IPF human lung fibroblasts. Reducing the activity or expression of TBK1 led to reduction in α-smooth muscle actin stress fiber levels by 40-60% and deposition of ECM components collagen I and fibronectin by 50% in TGF-ß-stimulated normal and IPF fibroblasts. YAP and TAZ are homologous mechanoregulatory profibrotic transcription cofactors known to regulate fibroblast activation. TBK1 knockdown or inhibition decreased the total and nuclear protein levels of YAP/TAZ. Additionally, low cell-cell contact and increased ECM substrate stiffness augmented the phosphorylation and activation of TBK1, consistent with cues that regulate YAP/TAZ. The action of TBK1 toward YAP/TAZ activation was independent of LATS1/2 and canonical downstream TBK1 signaling mediator IRF3 but dependent on proteasomal machinery of the cell. This study identifies TBK1 as a fibrogenic activator of human pulmonary fibroblasts, suggesting TBK1 may be a novel therapeutic target in pulmonary fibrosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/genética , Proteínas Serina-Treonina Quinases/genética , Transativadores/genética , Fatores de Transcrição/genética , Actinas/genética , Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Comunicação Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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