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1.
Am J Respir Crit Care Med ; 206(12): 1463-1479, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-35998281

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-ß (adenovirus transforming growth factor-ß) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-ß-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-ß, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.


Assuntos
Fibrose Pulmonar Idiopática , Inibidores de Proteínas Quinases , Animais , Humanos , Camundongos , Bleomicina/efeitos adversos , Fibroblastos/metabolismo , Fibrose , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/metabolismo , Fator de Crescimento Transformador beta/metabolismo
2.
Am J Respir Cell Mol Biol ; 67(4): 446-458, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35728045

RESUMO

Fibroblasts play a central role in the lung fibrotic process. Our recent study identified a novel subpopulation of lung fibroblasts expressing meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), antifibrotic properties of which were confirmed by murine lung fibrosis model. Meflin-expressing fibroblasts were resistant to fibrogenesis induced by TGF-ß (transforming growth factor-ß), but its underlying mechanisms remain unknown. In this study, evaluation of a silica-nanoparticle-induced lung fibrosis model confirmed the antifibrotic effect of meflin via the regulation of TGF-ß signaling. We conducted comparative gene expression profiling in lung fibroblasts, which identified growth differentiation factor 10 (Gdf10) encoding bone morphogenic protein 3b (BMP3b) as the most downregulated gene in meflin-deficient cells under the profibrotic condition with TGF-ß. We hypothesized that BMP3b can be an effector molecule playing an antifibrotic role downstream of meflin. As suggested by single-cell transcriptomic data, restricted expressions of Gdf10 (Bmp3b) in stromal cells including fibroblasts were confirmed. We examined possible antifibrotic properties of BMP3b in lung fibroblasts and demonstrated that Bmp3b-null fibroblasts were more susceptible to TGF-ß-induced fibrogenic changes. Furthermore, Bmp3b-null mice exhibited exaggerated lung fibrosis induced by silica-nanoparticles in vivo. We also demonstrated that treatment with recombinant BMP3B was effective against TGF-ß-induced fibrogenesis in fibroblasts, especially in the suppression of excessive extracellular matrix production. These lines of evidence suggested that BMP3b is a novel humoral effector molecule regulated by meflin which exerts antifibrotic properties in lung fibroblasts. Supplementation of BMP3B could be a novel therapeutic strategy for fibrotic lung diseases.


Assuntos
Fator 10 de Diferenciação de Crescimento , Fibrose Pulmonar , Animais , Fibroblastos/metabolismo , Fator 10 de Diferenciação de Crescimento/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Dióxido de Silício/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/metabolismo , Fatores de Crescimento Transformadores/farmacologia
3.
Circulation ; 144(4): 286-302, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34030460

RESUMO

BACKGROUND: Cellular diversity of the lung endothelium has not been systematically characterized in humans. We provide a reference atlas of human lung endothelial cells (ECs) to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium. METHODS: We reprocessed human control single-cell RNA sequencing (scRNAseq) data from 6 datasets. EC populations were characterized through iterative clustering with subsequent differential expression analysis. Marker genes were validated by fluorescent microscopy and in situ hybridization. scRNAseq of primary lung ECs cultured in vitro was performed. The signaling network between different lung cell types was studied. For cross-species analysis or disease relevance, we applied the same methods to scRNAseq data obtained from mouse lungs or from human lungs with pulmonary hypertension. RESULTS: Six lung scRNAseq datasets were reanalyzed and annotated to identify >15 000 vascular EC cells from 73 individuals. Differential expression analysis of EC revealed signatures corresponding to endothelial lineage, including panendothelial, panvascular, and subpopulation-specific marker gene sets. Beyond the broad cellular categories of lymphatic, capillary, arterial, and venous ECs, we found previously indistinguishable subpopulations; among venous EC, we identified 2 previously indistinguishable populations: pulmonary-venous ECs (COL15A1neg) localized to the lung parenchyma and systemic-venous ECs (COL15A1pos) localized to the airways and the visceral pleura; among capillary ECs, we confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1, and TBX2 and general capillary EC. We confirmed that all 6 endothelial cell types, including the systemic-venous ECs and aerocytes, are present in mice and identified endothelial marker genes conserved in humans and mice. Ligand-receptor connectome analysis revealed important homeostatic crosstalk of EC with other lung resident cell types. scRNAseq of commercially available primary lung ECs demonstrated a loss of their native lung phenotype in culture. scRNAseq revealed that endothelial diversity is maintained in pulmonary hypertension. Our article is accompanied by an online data mining tool (www.LungEndothelialCellAtlas.com). CONCLUSIONS: Our integrated analysis provides a comprehensive and well-crafted reference atlas of ECs in the normal lung and confirms and describes in detail previously unrecognized endothelial populations across a large number of humans and mice.


Assuntos
Biomarcadores , Células Endoteliais/metabolismo , Pulmão/metabolismo , Análise de Célula Única , Capilares , Biologia Computacional/métodos , Bases de Dados Genéticas , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pulmão/irrigação sanguínea , Pulmão/citologia , Microcirculação , Especificidade de Órgãos , Artéria Pulmonar , Veias Pulmonares , Análise de Célula Única/métodos , Transcriptoma
4.
Eur Respir J ; 58(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34049947

RESUMO

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis.We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis.scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-ß-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution.These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática , Fenótipo Secretor Associado à Senescência , Idoso , Animais , Bleomicina , Fibroblastos/patologia , Fibrose , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Camundongos
5.
Cancer Sci ; 110(6): 1959-1973, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004547

RESUMO

Activation of transforming growth factor ß (TGF-ß) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF-1α expression by protein phosphatase activity on dissociation of the E-cadherin/ß-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF-ß. By using lung cancer cells treated with HIF-1α stabilizers or carrying doxycycline-dependent HIF-1α deletion or point mutants, we investigated the role of stabilized HIF-1α expression on TGF-ß-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF-ß and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF-1α expression was inhibited. Stabilized HIF-1α protein expression inhibited the TGF-ß-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the HIF-1α-induced repression of the TGF-ß-stimulated appearance of EMT phenotypes. This is the first study to show a direct role of stabilized HIF-1α expression on inhibition of TGF-ß-induced EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fator de Crescimento Transformador beta1/farmacologia , Animais , Hipóxia Celular , Linhagem Celular , Linhagem Celular Transformada , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estabilidade Proteica , Interferência de RNA , Ratos
6.
Cancer Cell Int ; 16: 33, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27095949

RESUMO

BACKGROUND: Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial-mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. METHODS: Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. RESULTS: Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of ß-catenin translocation into the cytoplasm and nucleus. CONCLUSION: Our study strengthens the therapeutic possibility that compensatory induction of unphosphorylated PTEN may inhibit the acquisition of EMT phenotypes in lung cancer cells under persistent hypoxia.

7.
Cancer Sci ; 106(12): 1693-704, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26450531

RESUMO

Transforming growth factor ß (TGFß) causes the acquisition of epithelial-mesenchymal transition (EMT). Although the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) can negatively regulate many signaling pathways activated by TGFß, hyperactivation of these signaling pathways is observed in lung cancer cells. We recently showed that PTEN might be subject to TGFß-induced phosphorylation of its C-terminus, resulting in a loss of its enzyme activities; PTEN with an unphosphorylated C-terminus (PTEN4A), but not PTEN wild, inhibits TGFß-induced EMT. Nevertheless, whether or not the blockade of TGFß-induced EMT by the PTEN phosphatase activity might be attributed to the unphosphorylated PTEN C-terminus itself has not been fully determined. Furthermore, the lipid phosphatase activity of PTEN is well characterized, whereas the protein phosphatase activity has not been determined. By using lung cancer cells carrying PTEN domain deletions or point mutants, we investigated the role of PTEN protein phosphatase activities on TGFß-induced EMT in lung cancer cells. The unphosphorylated PTEN C-terminus might not directly retain the phosphatase activities and repress TGFß-induced EMT; the modification that keeps the PTEN C-terminus not phosphorylated might enable PTEN to retain the phosphatase activity. PTEN4A with G129E mutation, which lacks lipid phosphatase activity but retains protein phosphatase activity, repressed TGFß-induced EMT. Furthermore, the protein phosphatase activity of PTEN4A depended on an essential association between the C2 and phosphatase domains. These data suggest that the protein phosphatase activity of PTEN with an unphosphorylated C-terminus might be a therapeutic target to negatively regulate TGFß-induced EMT in lung cancer cells.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Pulmonares/patologia , PTEN Fosfo-Hidrolase/metabolismo , Western Blotting , Linhagem Celular Tumoral , Imunofluorescência , Humanos , Microscopia Confocal , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Transfecção , Fator de Crescimento Transformador beta/metabolismo
8.
Sci Rep ; 14(1): 5254, 2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438485

RESUMO

We investigated the effects of acute-phase intensive electrical muscle stimulation (EMS) on physical function in COVID-19 patients with respiratory failure requiring invasive mechanical ventilation (IMV) in the intensive care unit (ICU). Consecutive COVID-19 patients requiring IMV admitted to a university hospital ICU between January and April 2022 (EMS therapy group) or between March and September 2021 (age-matched historical control group) were included in this retrospective observational case-control study. EMS was applied to both upper and lower limb muscles for up to 2 weeks in the EMS therapy group. The study population consisted of 16 patients undergoing EMS therapy and 16 age-matched historical controls (median age, 71 years; 81.2% male). The mean period until initiation of EMS therapy after ICU admission was 3.2 ± 1.4 days. The EMS therapy group completed a mean of 6.2 ± 3.7 EMS sessions, and no adverse events occurred. There were no significant differences between the two groups in Medical Research Council sum score (51 vs. 53 points, respectively; P = 0.439) or ICU mobility scale at ICU discharge. Addition of upper and lower limb muscle EMS therapy to an early rehabilitation program did not result in improved physical function at ICU discharge in severe COVID-19 patients.


Assuntos
COVID-19 , Respiração Artificial , Humanos , Masculino , Idoso , Feminino , Estudos de Casos e Controles , Estudos Retrospectivos , COVID-19/terapia , Músculos
9.
Respir Med Case Rep ; 43: 101857, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37124053

RESUMO

We present a case of 79-year-old female with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) developed an acute exacerbation (AE) triggered by coronavirus disease 2019 (COVID-19). The patient was unresponsive to a combination therapy of remdesivir, dexamethasone, and tocilizumab. Given that a recent multicenter cohort study reported ILD as a poor prognostic contributor in patients with RA and COVID-19, there may be potentially a certain number of patients with AE of RA-ILD triggered by COVID-19. This case highlights the need for a discussion how to treat these patients in a daily clinical practice.

10.
Sci Rep ; 13(1): 14529, 2023 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-37666912

RESUMO

This prospective observational cohort study was performed to investigate the physical function and mental health trajectories of novel coronavirus disease 2019 (COVID-19) patients requiring invasive mechanical ventilation (IMV) after discharge from the intensive care unit (ICU). The study population consisted of 64 patients (median age, 60 years; 85.9% male; median IMV duration, 9 days). At ICU discharge, 28.1% of the patients had Medical Research Council (MRC) sum score < 48 points, and prolonged IMV was significantly associated with lower MRC sum score and handgrip strength. Symptoms were similar between groups at ICU discharge, and the symptoms most commonly reported as moderate-to-severe were impaired well-being (52%), anxiety (43%), tiredness (41%), and depression (35%). Although muscle strength and mobility status were significantly improved after ICU discharge, Edmonton Symptom Assessment System score did not improve significantly in the prolonged IMV group. EuroQol five-dimension five-level summary index was significantly lower in the prolonged than short IMV group at 6 months after ICU discharge. We found substantial negative physical function and mental health consequences in the majority of surviving COVID-19 patients requiring IMV, with prolonged period of IMV showing greater negative effects not only immediately but also at 6 months after discharge from the ICU.


Assuntos
COVID-19 , Força da Mão , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Saúde Mental , Estudos Prospectivos , Respiração Artificial , COVID-19/epidemiologia , COVID-19/terapia
11.
JCI Insight ; 8(4)2023 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-36626225

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.


Assuntos
Autofagia , Fibrose Pulmonar Idiopática , Macrófagos , MicroRNAs , Animais , Humanos , Camundongos , Autofagia/genética , Bleomicina/efeitos adversos , Homeostase , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos/metabolismo , MicroRNAs/genética , Mitocôndrias/metabolismo
12.
Front Med (Lausanne) ; 9: 815924, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35187001

RESUMO

Because severe coronavirus disease 2019 (COVID-19) affects the respiratory system and develops into respiratory failure, patients with pre-existing chronic lung disorders, such as idiopathic pulmonary fibrosis (IPF), are thought to be at high risk of death. Patients with IPF often suffer from a lethal complication, acute exacerbation (AE), a significant part of which is assumed to be triggered by respiratory viral infection. However, whether mild to moderate COVID-19 can trigger AE in patients with IPF remains unknown. This is the case report of a 60-year-old man with a 4-year history of IPF who successfully recovered from moderate COVID-19 but subsequently developed more severe respiratory failure, which was considered to be a COVID-19-triggered acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). It is important to be aware of the risk of AE-IPF after COVID-19 and to properly manage this deadly complication of IPF. Recent literature reporting cases with chronic interstitial lung diseases which developed respiratory failure by complications with COVID-19 is also reviewed and discussed.

13.
Intern Med ; 61(2): 233-236, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34744107

RESUMO

We herein report a case of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) triggered by COVID-19. An 87-year-old woman tested positive for COVID-19 on a polymerase chain reaction test, and computed tomography revealed ground-glass opacity (GGO) superimposed on a background pattern consistent with usual interstitial pneumonia. Considering these data, we diagnosed her with AE-IPF. She experienced worsening of dyspnea and expansion of the GGO. Therefore, we introduced high-dose steroids (methylprednisolone 250 mg/day for 3 days). After the treatment, the pulmonary infiltrates improved. She was discharged from our hospital without severe disability. High-dose steroids can be a viable treatment option for AE-IPF triggered by COVID-19.


Assuntos
COVID-19 , Fibrose Pulmonar Idiopática , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , SARS-CoV-2 , Esteroides
14.
Nat Commun ; 13(1): 494, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35078977

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.


Assuntos
Células Epiteliais Alveolares/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , RNA-Seq/métodos , Análise de Célula Única/métodos , Células A549 , Células Epiteliais Alveolares/classificação , Animais , Células Cultivadas , Análise por Conglomerados , Células Epiteliais/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Humanos , Pulmão/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença Pulmonar Obstrutiva Crônica/patologia , Transdução de Sinais/genética
15.
J Clin Med ; 10(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204119

RESUMO

Whether a patient with severe coronavirus disease (COVID-19) will be successfully liberated from mechanical ventilation (MV) early is important in the COVID-19 pandemic. This study aimed to characterize the time course of parameters and outcomes of severe COVID-19 in relation to the timing of liberation from MV. This retrospective, single-center, observational study was performed using data from mechanically ventilated COVID-19 patients admitted to the ICU between 1 March 2020 and 15 December 2020. Early liberation from ventilation (EL group) was defined as successful extubation within 10 days of MV. The trends of respiratory mechanics and laboratory data were visualized and compared between the EL and prolonged MV (PMV) groups using smoothing spline and linear mixed effect models. Of 52 admitted patients, 31 mechanically ventilated COVID-19 patients were included (EL group, 20 (69%); PMV group, 11 (31%)). The patients' median age was 71 years. While in-hospital mortality was low (6%), activities of daily living (ADL) at the time of hospital discharge were significantly impaired in the PMV group compared to the EL group (mean Barthel index (range): 30 (7.5-95) versus 2.5 (0-22.5), p = 0.048). The trends in respiratory compliance were different between patients in the EL and PMV groups. An increasing trend in the ventilatory ratio during MV until approximately 2 weeks was observed in both groups. The interaction between daily change and earlier liberation was significant in the trajectory of the thrombin-antithrombin complex, antithrombin 3, fibrinogen, C-reactive protein, lymphocyte, and positive end-expiratory pressure (PEEP) values. The indicator of physiological dead space increases during MV. The trajectory of markers of the hypercoagulation status, inflammation, and PEEP were significantly different depending on the timing of liberation from MV. These findings may provide insight into the pathophysiology of COVID-19 during treatment in the critical care setting.

16.
Physiol Rep ; 9(3): e14727, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527707

RESUMO

Long-noncoding RNAs (lncRNAs) have numerous biological functions controlling cell differentiation and tissue development. The knowledge about the role of lncRNAs in human lungs remains limited. Here we found the regulatory role of the terminal differentiation-induced lncRNA (TINCR) in bronchial cell differentiation. RNA in situ hybridization revealed that TINCR was mainly expressed in bronchial epithelial cells in normal human lung. We performed RNA sequencing analysis of normal human bronchial epithelial cells (NHBECs) with or without TINCR inhibition and found the differential expression of 603 genes, which were enriched for cell adhesion and migration, wound healing, extracellular matrix organization, tissue development and differentiation. To investigate the role of TINCR in the differentiation of NHBECs, we employed air-liquid interface culture and 3D organoid formation assay. TINCR was upregulated during differentiation, loss of TINCR significantly induced an early basal-like cell phenotype (TP63) and a ciliated cell differentiation (FOXJ1) in late phase and TINCR overexpression suppressed basal cell phenotype and the differentiation toward to ciliated cells. Critical regulators of differentiation such as SOX2 and NOTCH genes (NOTCH1, HES1, and JAG1) were significantly upregulated by TINCR inhibition and downregulated by TINCR overexpression. RNA immunoprecipitation assay revealed that TINCR was required for the direct bindings of Staufen1 protein to SOX2, HES1, and JAG1 mRNA. Loss of Staufen1 induced TP63, SOX2, NOTCH1, HES1, and JAG1 mRNA expressions, which TINCR overexpression suppressed partially. In conclusion, TINCR is a novel regular of bronchial cell differentiation, affecting downstream regulators such as SOX2 and NOTCH genes, potentially in coordination with Staufen1.


Assuntos
Brônquios/metabolismo , Diferenciação Celular , Células Epiteliais/metabolismo , RNA Longo não Codificante/metabolismo , Brônquios/citologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Regulação da Expressão Gênica , Humanos , Fenótipo , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais
17.
Front Med (Lausanne) ; 7: 603047, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425948

RESUMO

Cellular senescence is a cell fate implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Cellular senescence occurs in response to cellular stressors such as oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction. Whether these stresses induce cellular senescence or an alternative cell fate depends on the type and magnitude of cellular stress, but also on intrinsic factors regulating the cellular stress response. Non-coding RNAs, including both microRNAs and long non-coding RNAs, are key regulators of cellular stress responses and susceptibility to cellular senescence. In this review, we will discuss cellular mechanisms that contribute to senescence in IPF and COPD and highlight recent advances in our understanding of how these processes are influenced by non-coding RNAs. We will also discuss the potential therapeutic role for targeting non-coding RNAs to treat these chronic lung diseases.

18.
Nagoya J Med Sci ; 82(2): 301-313, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32581409

RESUMO

High-flow nasal cannula (HFNC) oxygen is a therapy that has demonstrated survival benefits in acute respiratory failure (ARF). However, the role of HFNC in ARF due to interstitial pneumonia (IP) is unknown. The aim of this study was to compare the effects of HFNC therapy and non-invasive positive pressure ventilation (NPPV) in ARF due to IP. This retrospective observational study included 32 patients with ARF due to IP who were treated with HFNC (n = 13) or NPPV (n = 19). The clinical characteristics, intubation rate and 30-day mortality were analyzed and compared between the HFNC group and the NPPV group. Predictors of 30-day mortality were evaluated using a logistic regression model. HFNC group showed higher mean arterial blood pressure (median 92 mmHg; HFNC group vs 74 mmHg; NPPV group) and lower APACHEII score (median 22; HFNC group vs 27; NPPV group) than NPPV group. There was no significant difference in the intubation rate at day 30 between the HFNC group and the NPPV group (8% vs 37%: p = 0.069); the mortality rate at 30 days was 23% and 63%, respectively. HFNC therapy was a significant determinant of 30-day mortality in univariate analysis, and was confirmed to be an independent significant determinant of 30-day mortality in multivariate analysis (odds ratio, 0.148; 95% confidence interval, 0.025-0.880; p = 0.036). Our findings suggest that HFNC therapy can be a possible option for respiratory management in ARF due to IP. The results observed here warrant further investigation of HFNC therapy in randomized control trials.


Assuntos
Hipóxia/terapia , Intubação Intratraqueal/estatística & dados numéricos , Doenças Pulmonares Intersticiais/terapia , Mortalidade , Oxigenoterapia/métodos , Fibrose Pulmonar/terapia , Insuficiência Respiratória/terapia , APACHE , Doença Aguda , Idoso , Cânula , Progressão da Doença , Feminino , Humanos , Hipóxia/etiologia , Doenças Pulmonares Intersticiais/complicações , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/métodos , Respiração com Pressão Positiva/métodos , Fibrose Pulmonar/complicações , Insuficiência Respiratória/etiologia , Estudos Retrospectivos , Resultado do Tratamento
19.
Intern Med ; 57(23): 3429-3432, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30101911

RESUMO

Squamous cell carcinoma (SCC) transformation has been identified as a mechanism of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib, in EGFR-mutated lung cancer. However, whether second- or third-generation TKIs can overcome resistance due to SCC transformation remains unclear. We herein report an EGFR-mutated lung adenocarcinoma undergoing transformation into SCC that exhibited a durable response to afatinib, which is a second-generation irreversible EGFR-TKI. We suggest that afatinib can be considered as a treatment option for EGFR-mutated tumor undergoing SCC transformation, particularly in the absence of a T790M mutation.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Afatinib/uso terapêutico , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adenocarcinoma de Pulmão/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Mutação
20.
Int J Chron Obstruct Pulmon Dis ; 12: 3541-3547, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29270008

RESUMO

Background: Non-small cell lung cancer (NSCLC) is the predominant cause of death in patients with COPD, and the severity of COPD in NSCLC patients is classified mainly as mild to moderate. Most advanced NSCLC patients with mild to moderate COPD are treated with chemotherapy; however, the feasibility for and prognosis after chemotherapy of these patients are not well understood. The aim of this study was to elucidate the impact of mild to moderate COPD on the feasibility for and prognosis after chemotherapy in NSCLC patients. Patients and methods: A retrospective review was performed on 268 NSCLC patients who received first-line chemotherapy from 2009 to 2014 in our institution. Finally, 85 evaluable patients were included in this study. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients with mild to moderate COPD and those without COPD (non-COPD). Results: Forty-three patients were classified as COPD (27 cases mild and 16 cases moderate) and 42 patients as non-COPD. The COPD group were older and had fewer never-smokers than the non-COPD group. The objective response rate did not differ between groups (p=0.14). There was no significant difference in overall survival between COPD and non-COPD groups (15.0 and 17.0 months, log-rank test p=0.57). In the multivariate Cox's proportional hazard model, the adjusted hazard ratio (HRadj) was statistically significant for male sex (HRadj =5.382, 95% CI: 1.496-19.359; p=0.010), pathological diagnosis of adenocarcinoma (HRadj =0.460, 95% CI: 0.223-0.948; p=0.035), and epithelial growth factor receptor negative mutation (HRadj =6.040, 95% CI: 1.158-31.497; p=0.033), but not for the presence of COPD (HRadj =0.661, 95% CI: 0.330-1.325; p=0.24). Toxicity profile in COPD group was favorable, as in the non-COPD group. Conclusion: Mild to moderate COPD did not have a significant deleterious impact on toxicity and prognosis in NSCLC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Distribuição de Qui-Quadrado , Estudos de Viabilidade , Feminino , Volume Expiratório Forçado , Humanos , Japão , Estimativa de Kaplan-Meier , Pulmão/fisiopatologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Espirometria , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
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