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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809111

RESUMO

Idiopathic pulmonary fibrosis (IPF) identifies a specific entity characterized by chronic, progressive fibrosing interstitial pneumonia of unknown cause, still lacking effective therapies. Growing evidence suggests that the biologic processes occurring in IPF recall those which orchestrate cancer onset and progression and these findings have already been exploited for therapeutic purposes. Notably, the incidence of lung cancer in patients already affected by IPF is significantly higher than expected. Recent advances in the knowledge of the cancer immune microenvironment have allowed a paradigm shift in cancer therapy. From this perspective, recent experimental reports suggest a rationale for immune checkpoint inhibition in IPF. Here, we recapitulate the most recent knowledge on lung cancer immune stroma and how it can be translated into the IPF context, with both diagnostic and therapeutic implications.


Assuntos
Fibrose Pulmonar Idiopática/imunologia , Neoplasias Pulmonares/imunologia , Pulmão/imunologia , Células Estromais/imunologia , Progressão da Doença , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Células Estromais/patologia , Tomografia Computadorizada por Raios X , Microambiente Tumoral/imunologia
2.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805743

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease.


Assuntos
Células Epiteliais/patologia , Fibrose Pulmonar Idiopática/genética , Metaloproteinase 14 da Matriz/genética , Alvéolos Pulmonares/metabolismo , Células A549 , Actinas/genética , Actinas/metabolismo , Animais , Bleomicina/administração & dosagem , Senescência Celular/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Metaloproteinase 14 da Matriz/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
3.
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
4.
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
6.
Am J Physiol Cell Physiol ; 320(5): C689-C695, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33471621

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease of unknown etiology with limited treatment options. It is characterized by repetitive injury to alveolar epithelial cells and aberrant activation of numerous signaling pathways. Recent evidence suggests that metabolic reprogramming, metabolic dysregulation, and mitochondria dysfunction are distinctive features of the IPF lungs. Through numerous mechanisms, metabolomic abnormalities in alveolar epithelial cells, myofibroblast, macrophages, and fibroblasts contribute to the abnormal collagen synthesis and dysregulated airway remodeling described in lung fibrosis. This review summarizes the metabolomic changes in amino acids, lipids, glucose, and heme seen in IPF lungs. Simultaneously, we provide new insights into potential therapeutic strategies by targeting a variety of metabolites.


Assuntos
Remodelação das Vias Aéreas , Metabolismo Energético , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Metabolômica , Mitocôndrias/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Aminoácidos/metabolismo , Animais , Fibroblastos/metabolismo , Fibroblastos/patologia , Glucose/metabolismo , Heme/metabolismo , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/fisiopatologia , Metabolismo dos Lipídeos , Lipidômica , Pulmão/patologia , Pulmão/fisiopatologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Mitocôndrias/patologia , Transdução de Sinais
7.
Am J Respir Cell Mol Biol ; 64(4): 453-464, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493091

RESUMO

Fibroblast activation is transient in successful wound repair but persistent in fibrotic pathologies. Understanding fibroblast deactivation during successful wound healing may provide new approaches to therapeutically reverse fibroblast activation. To characterize the gene programs that accompany fibroblast activation and reversal during lung fibrosis resolution, we used RNA sequencing analysis of flow sorted Col1α1-GFP-positive and CD45-, CD31-, and CD326-negative cells isolated from the lungs of young mice exposed to bleomycin. We compared fibroblasts isolated from control mice with those isolated at Days 14 and 30 after bleomycin exposure, representing the peak of extracellular matrix deposition and an early stage of fibrosis resolution, respectively. Bleomycin exposure dramatically altered fibroblast gene programs at Day 14. Principal component and differential gene expression analyses demonstrated the predominant reversal of these trends at Day 30. Upstream regulator and pathway analyses of reversing "resolution" genes identified novel candidate antifibrotic genes and pathways. Two genes from these analyses that were decreased in expression at Day 14 and reversed at Day 30, Aldh2 and Nr3c1, were selected for further analysis. Enhancement of endogenous expression of either gene by CRISPR activation in cultured human idiopathic pulmonary fibrosis fibroblasts was sufficient to reduce profibrotic gene expression, fibronectin deposition, and collagen gel compaction, consistent with roles for these genes in fibroblast deactivation. This combination of RNA sequencing analysis of freshly sorted fibroblasts and hypothesis testing in cultured idiopathic pulmonary fibrosis fibroblasts offers a path toward identification of novel regulators of lung fibroblast deactivation, with potential relevance to understanding fibrosis resolution and its failure in human disease.


Assuntos
Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Bleomicina , Sistemas CRISPR-Cas , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/patologia , Edição de Genes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Camundongos Transgênicos , RNA-Seq , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Remissão Espontânea , Transdução de Sinais , Fatores de Tempo , Transcriptoma
8.
PLoS One ; 16(1): e0245147, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33411718

RESUMO

BACKGROUND: Histopathologic factors predictive of nintedanib efficacy in idiopathic pulmonary fibrosis have not been studied. We aimed to describe the characteristics, focusing on histopathology, of idiopathic pulmonary fibrosis patients who did and did not respond to nintedanib. METHODS: This study retrospectively examined the clinicoradiopathologic features of 40 consecutive patients with surgical lung biopsy-confirmed idiopathic pulmonary fibrosis treated with nintedanib. Additionally, we compared the histopathologic scoring of 21 microscopic features between patients with functional or radiological progression and those with non-progression during 12 months of treatment. RESULTS: The histopathologic evaluation showed edematous changes in the interlobular septum as the only histologic finding observed more frequently in patients with both functional and radiological progression than in those without (58% vs. 14%, P = 0.007 and 50% vs. 0%, P = 0.003, respectively). Regarding per-year change, patients with edematous changes in the interlobular septum showed greater progression in median changes in spared area (-12%, interquartile range: [-25%--5%], vs. -3% [-7%-0%], P = 0.004) and reticular shadow (7% [3%-13%], vs. 0% [0%-5%], P = 0.041) on computed tomography. Functional and radiological progression-free survival were shorter in patients with edematous changes in the interlobular septum than in those without (6.6 months, 95% confidence interval: [5.9-25.3], vs. event <50%, [12.1-Not available], P = 0.0009, and 6.1 months, [5.2-6.6] vs. 14.5 months [7.8-not available], P<0.0001). CONCLUSIONS: Edematous changes in the interlobular septum may indicate poor nintedanib efficacy in idiopathic pulmonary fibrosis. Further studies are needed to validate these findings and address the mechanism behind ECIS.


Assuntos
Fibrose Pulmonar Idiopática , Indóis/administração & dosagem , Pulmão , Idoso , Biópsia , Intervalo Livre de Doença , Feminino , Humanos , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/terapia , Pulmão/patologia , Pulmão/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
9.
Biochem Biophys Res Commun ; 534: 99-106, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33316546

RESUMO

Interstitial pneumonia with autoimmune features (IPAF) is an unexplained disease state characterized by autoimmunity and pulmonary fibrosis. Exploring the pathogenesis of IPAF is helpful for the treatment of interstitial pneumonia and idiopathic pulmonary fibrosis. In this study, we observed that the lung Galectin-9 (Gal-9) of IPAF patients was significantly reduced, which was significantly related to lung dysfunction and abnormal humoral immunity. Moreover, an overreactive germinal center (GC) reaction in the lung lymph nodes (LNs) of Gal-9-deficient mice was found to be related to abnormally active follicular helper T cells (Tfh) cells. The lack of Gal-9 ligand in Tfh cells can lead to excessive transcriptional programming and differentiation and help GC B cells. Gal-9 deficiency caused an abnormal humoral immune response in mice, leading to excessive deposition of nonspecific autoantibodies in mice and chronic lung fibrosis. Our research reveals the important regulatory role of gal-9 in Tfh cells and a possible target for the treatment of IPAF.


Assuntos
Galectinas/imunologia , Fibrose Pulmonar Idiopática/imunologia , Imunidade Humoral , /imunologia , Animais , Autoanticorpos/sangue , Autoimunidade/imunologia , Estudos de Casos e Controles , Feminino , Galectinas/genética , Galectinas/metabolismo , Centro Germinativo/imunologia , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , /fisiologia
10.
Phytomedicine ; 81: 153428, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341025

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive fibrotic lung disease lacking a validated and effective therapy. Aberrant activation of the Wnt/ß-catenin signaling cascade plays the key role in the pathogenesis of IPF. Betulinic acid is a natural pentacyclic triterpenoid molecule that has excellent antitumor and antiviral activities. HYPOTHESIS: We hypothesized that BA has an anti-pulmonary fibrosis effect mediated by the suppression of the Wnt/ß-catenin pathway. Study design Pulmonary fibrosis markers were detected in vitro and in vivo to confirm the antifibrotic effect of BA. The Wnt/ß-catenin pathway-related proteins were overexpressed to determine the effect of BA on Wnt signaling. METHODS AND RESULTS: BA dose-dependently inhibited Wnt3a-induced fibroblast activation in vitro. Moreover, BA decreased Wnt3a- and LiCl-induced transcriptional activity, as assessed by the TOPFlash assay in fibroblasts, and repressed the expression of the Wnt target genes cyclin D1, axin 2, and S100A4. Further investigation indicated that BA restrained the nuclear accumulation of ß-catenin, mainly by increasing the phospho-ß-catenin ratio (S33/S37/T41 and S45), inhibited the phosphorylation of DVL2 and LRP, and decreased the levels of Wnt3a and LRP6. In agreement with the results of the in vitro assays, the in vivo experiments indicated that BA significantly decreased bleomycin-induced pulmonary fibrosis in mice and suppressed myofibroblast activation by inhibiting Wnt/ß-catenin signaling. CONCLUSION: BA may directly interfere with the Wnt/ß-catenin pathway to subsequently repress myofibroblast activation and pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Triterpenos Pentacíclicos/farmacologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Bleomicina/toxicidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
11.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L356-L367, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33325804

RESUMO

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed redox balance and increased production of reactive oxygen species (ROS), which is believed to contribute to epithelial injury and fibrotic lung scarring. The main pulmonary sources of ROS include mitochondria and NADPH oxidases (NOXs), of which the NOX4 isoform has been implicated in IPF. Non-receptor SRC tyrosine kinases (SFK) are important for cellular homeostasis and are often dysregulated in lung diseases. SFK activation by the profibrotic transforming growth factor-ß (TGF-ß) is thought to contribute to pulmonary fibrosis, but the relevant SFK isoform and its relationship to NOX4 and/or mitochondrial ROS in the context of profibrotic TGF-ß signaling is not known. Here, we demonstrate that TGF-ß1 can rapidly activate the SRC kinase FYN in human bronchial epithelial cells, which subsequently induces mitochondrial ROS (mtROS) production, genetic damage shown by the DNA damage marker γH2AX, and increased expression of profibrotic genes. Moreover, TGF-ß1-induced activation of FYN involves initial activation of NOX4 and direct cysteine oxidation of FYN, and both FYN and mtROS contribute to TGF-ß-induced induction of NOX4. NOX4 expression in lung tissues of IPF patients is positively correlated with disease severity, although FYN expression is down-regulated in IPF and does not correlate with disease severity. Collectively, our findings highlight a critical role for FYN in TGF-ß1-induced mtROS production, DNA damage response, and induction of profibrotic genes in bronchial epithelial cells, and suggest that altered expression and activation of NOX4 and FYN may contribute to the pathogenesis of pulmonary fibrosis.


Assuntos
Brônquios/metabolismo , Células Epiteliais/metabolismo , Mitocôndrias/metabolismo , NADPH Oxidase 4/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Brônquios/patologia , Células Epiteliais/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Mitocôndrias/patologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
13.
Arch. Soc. Esp. Oftalmol ; 95(12): 603-606, dic. 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-197759

RESUMO

Las distrofias en patrón de la retina son un grupo heterogéneo de maculopatías, en general, bilaterales y simétricas, que curiosamente se pueden asociar a diferentes enfermedades sistémicas. En este artículo se describe el caso de una paciente con distrofia en patrón unilateral que presentó asociada enfermedad de McArdle y fibrosis pulmonar idiopática


Retinal pattern dystrophies are a heterogeneous group of generally bilateral and symmetrical maculopathies that, curiously, can be associated with different systemic diseases. This article describes a patient with unilateral pattern dystrophies, as well as associated McArdle disease and idiopathic pulmonary fibrosis


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Degeneração Macular/patologia , Distrofias Retinianas/patologia , Doença de Depósito de Glicogênio Tipo V/patologia , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Degeneração Macular/diagnóstico por imagem , Distrofias Retinianas/diagnóstico por imagem , Distrofias Retinianas/complicações , Radiografia , Tomografia de Coerência Óptica , Fibrose Pulmonar Idiopática/complicações , Degeneração Macular/complicações , Doença de Depósito de Glicogênio Tipo V/complicações
14.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 212-217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093785

RESUMO

Background: Zonal aggregates of elastic fibres (zonal elastosis) and intraalveolar collagenosis with septal elastosis are histologic components of subpleural fibroelastosis of idiopathic pleuroparenchymal fibroelastosis (IPPFE). Zonal elastosis is considered to result from alveolar collapse, but this mechanism has not been fully justified. Methods: We immunohistochemically attempted to identify epithelial cells in zonal elastosis of 10 patients with IPPFE. The thickness of the zonal elastosis in relation to the total thickness of the fibroelastosis was examined to estimate the influence of zonal elastosis on the occurrence and development of IPPFE. Results: In 9 of the 10 patients, multi-cytokeratin-positive cells were found lining the inner surface of slit-like spaces embedded in the zonal elastosis. Zonal elastosis was predominant when fibroelastosis was < 1 mm thick but less predominant when it was ≥1 mm. Conclusion: The zonal elastosis was proven to result from alveolar collapse, which might be an initial lesion in IPPFE. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 212-217).


Assuntos
Tecido Elástico/patologia , Fibrose Pulmonar Idiopática/patologia , Alvéolos Pulmonares/metabolismo , Adulto , Idoso , Células Epiteliais Alveolares/química , Células Epiteliais Alveolares/patologia , Biomarcadores/análise , Tecido Elástico/química , Feminino , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Queratinas/análise , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/química , Estudos Retrospectivos , Adulto Jovem
15.
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
16.
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
17.
Nat Commun ; 11(1): 4659, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938936

RESUMO

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.


Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Médica Translacional
18.
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
19.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L675-L682, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877221

RESUMO

Mucosal surfaces are constantly exposed to a microbiome consisting of microorganisms that heavily influence human immunity and health. In the lung these microorganisms consist of bacteria, viruses, and fungi and exist in a relatively low biomass state. Bacterial communities of the lung modulate local inflammation and correlate with changes in pulmonary physiology and clinical outcomes in patients with lung disease. Instrumental to this progress has been the study of these bacterial communities in the pathogenesis of pulmonary fibrosis, a fatal and progressive disease culminating in respiratory failure. Key pathophysiological mechanisms in pulmonary fibrosis include recurrent idiopathic alveolar epithelial injury, unchecked collagen deposition, mucociliary dysfunction due to muc5b overexpression, hypoxia, and altered host defense. These key mechanisms and their related consequences promote severe progressive architectural lung destruction and loss of local homeostasis. As such, pulmonary fibrosis is an appropriate target disease for the study of the lung microbiome. Herein, we discuss recent advances in our understanding of the role of the lung microbiome in the pathogenesis of pulmonary fibrosis. We highlight fundamental clinical observations and mechanistic insights and identify crucial areas for further discovery science. An improved understanding of how the lung microbiome acts to influence outcomes in patients with pulmonary fibrosis will lead to enhanced therapies for this devastating lung disease.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Inflamação/patologia , Pulmão/patologia , Microbiota/fisiologia , Animais , Bactérias/patogenicidade , Progressão da Doença , Humanos , Inflamação/microbiologia , Pulmão/microbiologia
20.
J Comput Assist Tomogr ; 44(5): 667-672, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32842066

RESUMO

OBJECTIVE: The aim of the study was to compare the prevalence of diffuse pulmonary ossification (DPO) in idiopathic pulmonary fibrosis (IPF), systemic sclerosis (SSc)-related interstitial lung disease (ILD), and chronic hypersensitivity pneumonitis (HP). METHODS: High-resolution computed tomography (HRCT) from 71 IPF, 67 SSc-ILD, and 75 HP cases were independently evaluated by 2 thoracic radiologists blinded to patient data. Studies were assessed for the presence of DPO, HRCT scanning pattern, stigmata of granulomatous infection, and honeycombing. RESULTS: The prevalence of DPO was significantly higher in cases of IPF and SSc compared with HP, although there was no significant difference in prevalence between the IPF and SSc groups, even when accounting for the presence of prior granulomatous infection. Interobserver agreement for the presence of DPO was substantial. CONCLUSIONS: Although prevalence DPO on HRCT varies between some forms of ILD, the use of DPO to influence characterization of ILD should be considered with caution.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Ossificação Heterotópica/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Ossificação Heterotópica/patologia , Escleroderma Sistêmico/complicações , Adulto Jovem
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