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2.
Arch. bronconeumol. (Ed. impr.) ; 56(8): 506-513, ago. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-198191

RESUMO

INTRODUCTION: MicroRNA-7 (miR-7) has a suppressive role in lung cancer and alterations in its DNA methylation may contribute to tumorigenesis. As COPD patients with emphysema have a higher risk of lung cancer than other COPD phenotypes, we compared the miR-7 methylation status among smoker subjects and patients with various COPD phenotypes to identify its main determinants. METHODS: 30 smoker subjects without airflow limitation and 136 COPD patients without evidence of cancer were recruited in a prospective study. Clinical and functional characteristics were assessed and patients were classified into: frequent exacerbator, emphysema, chronic bronchitis and asthma COPD overlap (ACO). DNA collected from buccal epithelial samples was isolated and bisulfite modified. miR-7 methylation status was evaluated by quantitative methylation-specific polymerase chain reaction (qMSP). RESULTS: miR-7 Methylated levels were higher in COPD patients than in smokers without airflow limitation (23.7 ± 12.4 vs. 18.5 ± 8.8 %, p = 0.018). Among COPD patients, those with emphysema had higher values of methylated miR-7 (27.1 ± 10.2 %) than those with exacerbator (19.4 ± 9.9 %, p = 0.004), chronic bronchitis (17.3 ± 9.0 %, p = 0.002) or ACO phenotypes (16.0 ± 7.2 %, p = 0.010). After adjusting for clinical parameters, differences between emphysematous patients and those with other phenotypes were retained. In COPD patients, advanced age, mild-moderate airflow limitation, reduced diffusing capacity and increased functional residual capacity were identified as independent predictors of methylated miR-7 levels. CONCLUSION: The increase of miR-7 methylation levels experienced by COPD patients occurs mainly at the expense of the emphysema phenotype, which might contribute to explain the higher incidence of lung cancer in these patients


INTRODUCCIÓN: El microRNA-7 (miR-7) tiene un papel supresor en el cáncer de pulmón, y las alteraciones en la metilación de su DNA podrían contribuir a la tumorogénesis. Como los pacientes con EPOC y enfisema presentan un mayor riesgo de sufrir cáncer de pulmón frente a otros fenotipos de EPOC, comparamos la metilación de miR-7 entre los pacientes fumadores y los pacientes con varios fenotipos de EPOC para identificar sus factores determinantes principales. MÉTODOS: Se reclutaron para un estudio prospectivo 30 sujetos fumadores sin restricciones en el flujo aéreo y 136 pacientes con EPOC sin evidencia de cáncer. Se valoraron las características clínicas y funcionales y se clasificaron a los pacientes en: exacerbaciones frecuentes, enfisema, bronquitis crónica y solapamiento de asma y EPOC (ACO, por sus siglas en inglés). Se recogió ADN a partir de muestras de epitelio bucal, se aisló y se modificó con bisulfito. El estado de metilación del miR-7 se evaluó mediante la reacción cuantitativa en cadena de la polimerasa específica de la metilación (qMPS por sus siglas en inglés). RESULTADOS: Los niveles de metilación del miR-7 fueron más altos en los pacientes con EPOC que en los fumadores sin restricciones en el flujo aéreo (23,7 ± 12,4 frente a 18,5 ± 8,8%, p = 0,018). Entre los pacientes con EPOC, aquellos con enfisema presentaban valores más altos de miR-7 metilado (27,1 ± 10,2%) que aquellos con exacerbaciones (19,4 ± 9,9%, p = 0,004), bronquitis crónica (17,3 ± 9,0%, p = 0,002) o los fenotipos ACO (16,0 ± 7,2%, p = 0,010). Tras ajustar los resultados a los parámetros clínicos, las diferencias entre los pacientes enfisematosos y aquellos con otros fenotipos permanecieron. En los pacientes con EPOC, se identificaron como predictores independientes de los niveles de metilación del miR-7 a: la edad avanzada, limitación al flujo aéreo leve-moderada, capacidad de difusión reducida y capacidad residual funcional aumentada. CONCLUSIÓN: El aumento de los niveles de metilación del miR-7 que experimentan los pacientes con EPOC ocurre principalmente a expensas del fenotipo con enfisema, lo que podría contribuir a explicar la mayor incidencia de cáncer de pulmón en estos pacientes


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Metilação , MicroRNAs/metabolismo , Enfisema Pulmonar/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Estudos Prospectivos , Fenótipo
3.
Am J Respir Cell Mol Biol ; 63(4): 452-463, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32663413

RESUMO

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1-derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.


Assuntos
Elastase Pancreática/metabolismo , Peptídeos/metabolismo , Enfisema Pulmonar/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose/fisiologia , Simulação por Computador , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Alvéolos Pulmonares/metabolismo , Fumaça/efeitos adversos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Sci Rep ; 10(1): 10949, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616814

RESUMO

Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in the fibrillin-1 gene. Pulmonary functional abnormalities, such as emphysema and restrictive lung diseases, are frequently observed in patients with MFS. However, the pathogenesis and molecular mechanism of pulmonary involvement in MFS patients are underexplored. Notch signaling is essential for lung development and the airway epithelium regeneration and repair. Therefore, we investigated whether Notch3 signaling plays a role in pulmonary emphysema in MFS. By using a murine model of MFS, fibrillin-1 hypomorphic mgR mice, we found pulmonary emphysematous-appearing alveolar patterns in the lungs of mgR mice. The septation in terminal alveoli of lungs in mgR mice was reduced compared to wild type controls in the early lung development. These changes were associated with increased Notch3 activation. To confirm that the increased Notch3 signaling in mgR mice was responsible for structure alterations in the lungs, mice were treated with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglucine t-butyl ester (DAPT), a γ-secretase inhibitor, which inhibits Notch signaling. DAPT treatment reduced lung cell apoptosis and attenuated pulmonary alteration in mice with MFS. This study indicates that Notch3 signaling contributes to pulmonary emphysema in mgR mice. Our results may have the potential to lead to novel strategies to prevent and treat pulmonary manifestations in patients with MFS.


Assuntos
Modelos Animais de Doenças , Síndrome de Marfan/complicações , Enfisema Pulmonar/patologia , Receptor Notch3/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Receptor Notch3/genética
5.
Am J Respir Crit Care Med ; 202(7): 983-995, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32515984

RESUMO

Rationale: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of HIF-2α (hypoxia-inducible factor-2α)-regulated genes, and tobacco smoke decreases pulmonary HIF-2α concentrations. These findings suggest that decreased HIF-2α expression is important in the development of emphysema.Objectives: The objective of this study was to evaluate the roles of endothelial-cell (EC) HIF-2α in the pathogenesis of emphysema in mice.Methods: Mouse lungs were examined for emphysema after either the loss or the overexpression of EC Hif-2α. In addition, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for HGF (hepatocyte growth factor), a protein involved in alveolar development and homeostasis. Lungs from patients with emphysema were measured for endothelial HIF-2α expression.Measurements and Main Results: EC Hif-2α deletion resulted in emphysema in association with fewer ECs and pericytes. After SU5416 exposure, EC Hif-2α-knockout mice developed more severe emphysema, whereas EC Hif-2α-overexpressing mice were protected. EC Hif-2α-knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2α expression.Conclusions: Here, we demonstrate a unique protective role for pulmonary endothelial HIF-2α and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2α may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2α may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Endoteliais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/metabolismo , Enfisema Pulmonar/genética , Inibidores da Angiogênese/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Desferroxamina/farmacologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Indóis/toxicidade , Quelantes de Ferro/farmacologia , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microvasos , Pericitos/metabolismo , Circulação Pulmonar , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Pirróis/toxicidade , Fumaça/efeitos adversos
6.
Am J Respir Cell Mol Biol ; 63(1): 67-78, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32101459

RESUMO

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. C/EBPα (CCAAT/enhancer binding protein-α), a transcription factor, is required for lung maturation during development, and is also important for lung homeostasis after birth, including the maintenance of serine protease/antiprotease balance in the bronchiolar epithelium. This study aimed to show the roles of C/EBPα in the distal airway during chronic cigarette smoke exposure in mice and in the small airways in smokers. In a model of chronic smoke exposure using epithelial cell-specific C/EBPα-knockout mice, significant pathological phenotypes, such as higher protease activity, impaired ciliated cell regeneration, epithelial cell barrier dysfunction via reduced zonula occludens-1 (Zo-1), and decreased alveolar attachments, were found in C/EBPα-knockout mice compared with control mice. We found that Spink5 (serine protease inhibitor kazal-type 5) gene (encoding lymphoepithelial Kazal-type-related inhibitor [LEKTI], an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model. Finally, we showed that daily antiprotease treatment counteracted the phenotypes of C/EBPα-knockout mice. In human studies, CEBPA (CCAAT/enhancer binding protein-α) gene expression in the lung was downregulated in patients with emphysema, and six smokers with centrilobular emphysema (CLE) showed a significant reduction in LEKTI in the small airways compared with 22 smokers without CLE. LEKTI downregulation in the small airways was associated with disease development during murine small airway injury and CLE in humans, suggesting that LEKTI might be a key factor linking small airway injury to the development of emphysema.


Assuntos
Pulmão/metabolismo , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Serina Proteases/metabolismo , Animais , Bronquíolos/metabolismo , Bronquíolos/patologia , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Fumar/metabolismo
7.
Bull Exp Biol Med ; 168(3): 334-340, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31940128

RESUMO

The changes in endothelial progenitor cells and progenitor cells of angiogenesis, pericytes and smooth muscle cells, were studied in female C57BL/6 mice with a combination of metabolic impairments induced by injections of sodium glutamate and lung emphysema modeled by the administration of cigarette smoke extract. It was observed that sodium glutamate significantly enhances pathological changes in the lungs (inflammation and lung emphysema) induced by the administration of cigarette smoke extract. Recruiting of endothelial progenitor cells (CD45-CD31+CD34+ and CD31+CD34+CD146-) and progenitor cells of angiogenesis (CD45-CD117+CD309+) was registered in the injured lungs. Angiogenesis impairment induced by combined exposure is related to altered migration of pericytes (CD31-CD34-CD146+) and smooth muscle cells (CD31-CD34+CD146+) in emphysema-like enlarged lung tissue.


Assuntos
Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Pericitos/citologia , Pericitos/metabolismo , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Animais , Antígenos CD34/metabolismo , Antígeno CD146/metabolismo , Fumar Cigarros/efeitos adversos , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Feminino , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo
8.
Am J Respir Crit Care Med ; 201(8): 934-945, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31834999

RESUMO

Rationale: The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown.Objectives: We aimed to define the impact of FSTL-1 attenuation on lung structure and function and to identify FSTL-1-regulated transcriptional pathways in the lung. Further, we aimed to analyze the association of FSTL-1 SNPs with lung disease.Methods: FSTL-1 hypomorphic (FSTL-1 Hypo) mice underwent lung morphometry, pulmonary function testing, and micro-computed tomography. Fstl1 expression was determined in wild-type lung cell populations from three independent research groups. RNA sequencing of wild-type and FSTL-1 Hypo mice identified FSTL-1-regulated gene expression, followed by validation and mechanistic in vitro examination. FSTL1 SNP analysis was performed in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort.Measurements and Main Results: FSTL-1 Hypo mice developed spontaneous emphysema, independent of smoke exposure. Fstl1 is highly expressed in the lung by mesenchymal and endothelial cells but not immune cells. RNA sequencing of whole lung identified 33 FSTL-1-regulated genes, including Nr4a1, an orphan nuclear hormone receptor that negatively regulates NF-κB (nuclear factor-κB) signaling. In vitro, recombinant FSTL-1 treatment of macrophages attenuated NF-κB p65 phosphorylation in an Nr4a1-dependent manner. Within the COPDGene cohort, several SNPs in the FSTL1 region corresponded to chronic obstructive pulmonary disease and lung function.Conclusions: This work identifies a novel role for FSTL-1 protecting against emphysema development independent of smoke exposure. This FSTL-1-deficient emphysema implicates regulation of immune tolerance in lung macrophages through Nr4a1. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-κB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.


Assuntos
Proteínas Relacionadas à Folistatina/genética , Pulmão/diagnóstico por imagem , Enfisema Pulmonar/genética , Fumaça/efeitos adversos , Animais , Células Endoteliais/metabolismo , Proteínas Relacionadas à Folistatina/farmacologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Mutação , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Tabaco , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Microtomografia por Raio-X
9.
Am J Respir Crit Care Med ; 201(5): 540-554, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31661293

RESUMO

Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.


Assuntos
Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Fumar/epidemiologia , alfa 1-Antitripsina/genética , Adulto , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu , Feminino , Volume Expiratório Forçado , Genótipo , Heterozigoto , Hispano-Americanos , Humanos , Focalização Isoelétrica , Masculino , Fluxo Máximo Médio Expiratório , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatologia , Tomografia Computadorizada por Raios X , Capacidade Vital , alfa 1-Antitripsina/metabolismo
10.
Int J Chron Obstruct Pulmon Dis ; 14: 2507-2516, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814716

RESUMO

Background: Oxidative stress is one of the important mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD). Irisin is a type of myokine secreted from the muscle during exercise and acts against oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with antioxidant properties. Here, we examined the emphysema suppressive effects of the exercise-irisin-Nrf2 axis in mice. Methods: Mice were divided into three groups, namely, the control, smoking, and exercise + smoking groups. All mice from the smoking and exercise + smoking groups were exposed to cigarette smoke once a day. The mice from the exercise + smoking group were adapted to a treadmill once a day. To investigate the Nrf2 cascade, after 12 weeks, serum irisin concentration and Nrf2 and heme oxygenase-1 (HO-1) expression in the lung homogenate were determined. To evaluate cigarette smoke-induced COPD, the number of inflammatory cells in bronchoalveolar lavage fluid (BALF), mean linear intercept (MLI), and destructive index in the lung tissue were examined. Results: Serum irisin concentration and the expression levels of Nrf2 and HO-1 in the lung homogenate were significantly higher in mice from the exercise + smoking group than in those from the control and smoking groups. The proportion of neutrophils in the BALF was significantly lower in the exercise + smoking group than in the smoking group. The MLI and destructive index were also significantly smaller in mice from the exercise + smoking group than mice from the smoking group. Conclusion: Irisin secreted from the muscle during exercise may exert protective effects against oxidative stress via Nrf2 and HO-1, and ameliorate emphysema of cigarette smoke-induced COPD. The exercise-irisin-Nrf2 axis may serve as a novel target for COPD treatment.


Assuntos
Terapia por Exercício , Fibronectinas/sangue , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Doença Pulmonar Obstrutiva Crônica/terapia , Enfisema Pulmonar/prevenção & controle , Produtos do Tabaco , Animais , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Pulmão/fisiopatologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatologia , Transdução de Sinais , Fumaça
11.
Int J Chron Obstruct Pulmon Dis ; 14: 2697-2709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819402

RESUMO

Purpose: Elastin peptides (EP) can induce lung inflammation and emphysema. Erythromycin has been shown to decrease acute exacerbation frequency and delay lung function decline in chronic obstructive pulmonary disease patients and ameliorate emphysema in murine models; however, the mechanism remains unclear. We aimed to observe the preventive and immunomodulatory effects of erythromycin in a mouse model of EP-induced emphysema. Methods: In the in vivo study, Balb/c mice were treated with EP intranasally on day 0, and then administered erythromycin (100 mg/kg) or vehicle orally on day 1, which was continued every other day. Mice exposed to cigarette smoke were used as an emphysema positive control. The severity of emphysema and inflammation in the lungs of EP-exposed mice with or without erythromycin treatment were observed on day 40 after EP administration. In the in vitro study, naïve CD4+T cells were isolated from healthy mice spleens and stimulated by EP with or without erythromycin incubation. Flow cytometry was used to measure the proportions of Th1, Th17, and Treg cells. ELISA was used to detect cytokine levels of IFN-γ, IL-17, IL-6, and TGF-ß. Transcript levels of Ifnγ, IL17a, and Foxp3 were evaluated by qRT-PCR. Results: After exposure to EP, Th1 and Th17 cell percentages and the levels of inflammatory cytokines increased in vivo and in vitro, while Treg cells decreased in vivo. Erythromycin reduced IFN-γ, IL-17, IL-6 inflammatory cytokines, MLI, and the inflammation score in the lungs of EP-exposed mice. In vitro, erythromycin also limited Th17 and Th1 cell differentiation and downregulated transcript levels of Ifnγ and IL17a in the EP-stimulated CD4+T cells. Conclusion: The Th1 and Th17 cell responses were increased in EP-induced emphysema. Prophylactic use of erythromycin effectively ameliorated emphysema and modulated CD4+T cells responses in EP-induced lung inflammation in mice.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Citocinas/metabolismo , Elastina , Eritromicina/farmacologia , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos , Pneumonia/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/genética , Modelos Animais de Doenças , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
12.
Biosci Rep ; 39(11)2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31702007

RESUMO

OBJECTIVES: The present study aimed at investigating the therapeutic effect of Salidroside on skeletal muscle atrophy in a rat model of cigarette smoking-induced chronic obstructive pulmonary disease (COPD) and its potential mechanisms. METHODS: Male Wistar rats were randomized, and treated intraperitoneally (IP) with vehicle (injectable water) or a low, medium or high dose of Salidroside, followed by exposure to cigarette smoking daily for 16 weeks. A healthy control received vehicle injection and air exposure. Their lung function, body weights and gastrocnemius (GN) weights, grip strength and cross-section area (CSA) of individual muscular fibers in the GN were measured. The levels of TNF-α, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) in serum and GN tissues as well as myostatin and myogenin expression in GN tissues were measured. RESULTS: In comparison with that in the healthy control, long-term cigarette smoking induced emphysema, significantly impaired lung function, reduced body and GN weights and CSA values in rats, accompanied by significantly increased levels of TNF-α, IL-6 and MDA, but decreased levels of SOD and GSH in serum and GN tissues. Furthermore, cigarette smoking significantly up-regulated myostatin expression, but down-regulated myogenin expression in GN tissues. Salidroside treatment decreased emphysema, significantly ameliorated lung function, increased antioxidant, but reduced MDA, IL-6 and TNF-α levels in serum and GN tissues of rats, accompanied by decreased myostain, but increased myogenin expression in GN tissues. CONCLUSION: Salidroside mitigates the long-term cigarette smoking-induced emphysema and skeletal muscle atrophy in rats by inhibiting oxidative stress and inflammatory responses and regulating muscle-specific transcription factor expression.


Assuntos
Regulação para Baixo/fisiologia , Glucosídeos/farmacologia , Atrofia Muscular/metabolismo , Miogenina/metabolismo , Miostatina/metabolismo , Fenóis/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Regulação para Cima/fisiologia , Animais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Masculino , Músculo Esquelético/metabolismo , Enfisema Pulmonar/metabolismo , Ratos , Ratos Wistar , Fumaça/efeitos adversos , Fumar/efeitos adversos , Tabaco/efeitos adversos
13.
Sci Rep ; 9(1): 14848, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619733

RESUMO

Cigarette smoke exposure is a leading cause of chronic obstructive pulmonary disease (COPD), a major health issue characterized by airway inflammation with fibrosis and emphysema. Here we demonstrate that acute exposure to cigarette smoke causes respiratory barrier damage with the release of self-dsDNA in mice. This triggers the DNA sensor cGAS (cyclic GMP-AMP synthase) and stimulator of interferon genes (STING), driving type I interferon (IFN I) dependent lung inflammation, which are attenuated in cGAS, STING or type I interferon receptor (IFNAR) deficient mice. Therefore, we demonstrate a critical role of self-dsDNA release and of the cGAS-STING-type I interferon pathway upon cigarette smoke-induced damage, which may lead to therapeutic targets in COPD.


Assuntos
DNA/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Pneumonia/metabolismo , Enfisema Pulmonar/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sequências Repetitivas de Ácido Nucleico
14.
J Clin Invest ; 129(10): 4290-4304, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483291

RESUMO

Electronic nicotine delivery systems (ENDS) or e-cigarettes have emerged as a popular recreational tool among adolescents and adults. Although the use of ENDS is often promoted as a safer alternative to conventional cigarettes, few comprehensive studies have assessed the long-term effects of vaporized nicotine and its associated solvents, propylene glycol (PG) and vegetable glycerin (VG). Here, we show that compared with smoke exposure, mice receiving ENDS vapor for 4 months failed to develop pulmonary inflammation or emphysema. However, ENDS exposure, independent of nicotine, altered lung lipid homeostasis in alveolar macrophages and epithelial cells. Comprehensive lipidomic and structural analyses of the lungs revealed aberrant phospholipids in alveolar macrophages and increased surfactant-associated phospholipids in the airway. In addition to ENDS-induced lipid deposition, chronic ENDS vapor exposure downregulated innate immunity against viral pathogens in resident macrophages. Moreover, independent of nicotine, ENDS-exposed mice infected with influenza demonstrated enhanced lung inflammation and tissue damage. Together, our findings reveal that chronic e-cigarette vapor aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. Notably, alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the vehicle solvents used in e-cigarettes.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Imunidade Inata/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Adolescente , Adulto , Animais , Modelos Animais de Doenças , Feminino , Homeostase , Humanos , Lipidômica , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Fosfolipídeos/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Fumaça/efeitos adversos , Solventes/administração & dosagem , Solventes/efeitos adversos
15.
Nutrients ; 11(9)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470503

RESUMO

Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Isoflavonas/farmacologia , Pulmão/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Fumaça , Produtos do Tabaco , beta-Glucanas/farmacologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais
16.
Respir Res ; 20(1): 200, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477092

RESUMO

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease resulting in respiratory failure and represents the third leading cause of global death. The two classical phenotypes of COPD are chronic bronchitis and emphysema. Owing to similarities between chronic bronchitis and the autosomal-recessive disease Cystic Fibrosis (CF), a significant body of research addresses the hypothesis that dysfunctional CF Transmembrane Conductance Regulator (CFTR) is implicated in the pathogenesis of COPD. Much less attention has been given to emphysema in this context, despite similarities between the two diseases. These include early-onset cellular senescence, similar comorbidities, and the finding that CF patients develop emphysema as they age. To determine a potential role for CFTR dysfunction in the development of emphysema, Cftr+/+ (Wild-type; WT), Cftr+/- (heterozygous), and Cftr-/- (knock-out; KO) mice were aged or exposed to cigarette smoke and analyzed for airspace enlargement. Aged knockout mice demonstrated increased alveolar size compared to age-matched wild-type and heterozygous mice. Furthermore, both heterozygous and knockout mice developed enlarged alveoli compared to their wild-type counterparts following chronic smoke exposure. Taken into consideration with previous findings that cigarette smoke leads to reduced CFTR function, our findings suggest that decreased CFTR expression sensitizes the lung to the effects of cigarette smoke. These findings may caution normally asymptomatic CF carriers against exposure to cigarette smoke; as well as highlight emphysema as a future challenge for CF patients as they continue to live longer. More broadly, our data, along with clinical findings, may implicate CFTR dysfunction in a pathology resembling accelerated aging.


Assuntos
Envelhecimento/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/biossíntese , Enfisema Pulmonar/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Expressão Gênica , Exposição por Inalação/efeitos adversos , Camundongos , Camundongos Knockout , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/patologia
17.
Int J Biochem Cell Biol ; 116: 105598, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31499176

RESUMO

Chronic obstructive pulmonary disease (COPD) is characterised by an accelerated decline in airway function with age compared to age-matched non-smokers. There is increasing evidence that this is due to small airway disease rather than from emphysema, especially in the early stages of the disease. Small airways (<2 mm internal diameter) are narrowed in COPD with thickening and distortion of the airway wall and peribronchiolar fibrosis. In addition, loss of elasticity in alveolar attachments and mucus hypersecretion contribute to the airway narrowing and closure, leading to air trapping. The mechanisms of peribronchiolar fibrosis are poorly understood and small airway fibroblasts have not been characterised. In small airways of COPD patients the fibroblasts are profibrotic, pro-inflammatory and senescent. There is a reduction in the anti-ageing molecules sirtuin-1 and -6, which are regulated by specific microRNAs that are increased in COPD cells. It is plausible that extracellular vesicles from senescent airway epithelium transmit senescent signals to airway fibroblasts to stimulate fibrosis and inflammation. Small airways fibrosis is a target for new drug development that inhibit growth factor receptors, new antioxidants and particularly those that are targeted to mitochondria and inhibitors of cellular senescence or senolytic therapies.


Assuntos
Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Fibrose Pulmonar/genética , Sistema Respiratório/metabolismo , Sirtuína 1/genética , Sirtuínas/genética , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Senescência Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Transdução de Sinais , Sirtuína 1/metabolismo , Sirtuínas/metabolismo
18.
EBioMedicine ; 46: 305-316, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383554

RESUMO

BACKGROUND: Cigarette smoke is the main risk factor of pulmonary emphysema development, which is characterized by alveolar wall destruction. Mitochondria are important for alveolar type II (ATII) cell metabolism due to ATP generation. METHODS: We isolated ATII cells from control non-smoker and smoker organ donors, and after lung transplant of patients with emphysema to determine mitochondrial function, dynamics and mitochondrial (mt) DNA damage. FINDINGS: We found high mitochondrial superoxide generation and mtDNA damage in ATII cells in emphysema. This correlated with decreased mtDNA amount. We also detected high TOP1-cc and low TDP1 levels in mitochondria in ATII cells in emphysema. This contributed to the decreased resolution of TOP1-cc leading to accumulation of mtDNA damage and mitochondrial dysfunction. Moreover, we used lung tissue obtained from areas with mild and severe emphysema from the same patients. We found a correlation between the impaired fusion and fission as indicated by low MFN1, OPA1, FIS1, and p-DRP1 levels and this disease severity. We detected lower TDP1 expression in severe compared to mild emphysema. INTERPRETATION: We found high DNA damage and impairment of DNA damage repair in mitochondria in ATII cells isolated from emphysema patients, which contribute to abnormal mitochondrial dynamics. Our findings provide molecular mechanisms of mitochondrial dysfunction in this disease. FUND: This work was supported by National Institutes of Health (NIH) grant R01 HL118171 (B.K.) and the Catalyst Award from the American Lung Association (K.B.).


Assuntos
Células Epiteliais Alveolares/metabolismo , Mitocôndrias/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Trifosfato de Adenosina/biossíntese , Dano ao DNA , DNA Mitocondrial , Progressão da Doença , Metabolismo Energético , Humanos , Mitocôndrias/genética , Estresse Oxidativo , Diester Fosfórico Hidrolases/metabolismo , Transporte Proteico , Enfisema Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Fumaça/efeitos adversos , Superóxidos/metabolismo
19.
Inflamm Res ; 68(11): 957-968, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31468083

RESUMO

OBJECTIVE AND DESIGN: Chronic exposure to cigarette smoke promotes airway inflammation and emphysema accompanied by enhanced CD8+ interferon (IFN)-γ+ T(Tc1) and CD8+ interleukin (IL)-17+ T(Tc17) cell responses. The mammalian target of rapamycin (mTOR) has been involved in the pathogenesis of emphysema. Inhibiting mTOR by rapamycin has been reported to alleviate emphysema, but the mechanism is not fully understood. We aimed to explore the effect of rapamycin on Tc1 and Tc17 cell responses induced by cigarette smoke exposure. MATERIALS: Male C57BL/6 mice were exposed to cigarette smoke or room air for 24 weeks. Half of the smoke-exposed mice received rapamycin in the last 12 weeks. The severity of emphysema in those mice was evaluated by mean linear intercept (MLI), mean alveolar airspace area (MAA) and destructive index (DI). Bronchoalveolar lavage was collected and analyzed. Phosphorylated (p-) mTOR in CD8+ T cells, Tc1 and Tc17 cells were detected by flow cytometry. The relative expression of p-mTOR in lungs was determined by western blot analysis. IFN-γ and IL-17A levels were detected by enzyme-linked immunosorbent assays. IFN-γ, mTOR and RAR-related orphan receptor (ROR)γt mRNA levels were evaluated by the real-time polymerase chain reaction. RESULTS: Elevated p-mTOR expression in CD8+ T cells and lung tissue was accompanied by the enhanced Tc1 and Tc17 cell responses in lungs of mice exposed to cigarette smoke. Rapamycin reduced inflammatory cells in BALF and decreased MLI, DI and MAA in lungs. Rapamycin decreased p-mTOR expression, and down-regulation of mTOR and RORγt mRNA levels along with the attenuation of Tc1 and Tc17 cell responses in mice with emphysema. CONCLUSIONS: The mTOR was activated in CD8+ T cells accompanied by the enhanced Tc1 and Tc17 cell responses in cigarette smoke-related pulmonary inflammation. Rapamycin ameliorated emphysema and attenuated Tc1 and Tc17 cell responses probably caused by inhibiting mTOR in cigarette smoke-exposed mice.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Enfisema Pulmonar/imunologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Sirolimo/uso terapêutico , Fumaça , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Tabaco , Produtos do Tabaco
20.
Am J Physiol Lung Cell Mol Physiol ; 317(6): L791-L804, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31313618

RESUMO

Pulmonary emphysema is characterized by alveolar type II (ATII) cell death, destruction of alveolar wall septa, and irreversible airflow limitation. Cigarette smoke induces oxidative stress and is the main risk factor for this disease development. ATII cells isolated from nonsmokers, smokers, and patients with emphysema were used for this study. ATII cell apoptosis in individuals with this disease was detected. DJ-1 and S100A8 have cytoprotective functions against oxidative stress-induced cell injury. Reduced DJ-1 and S100A8 interaction was found in ATII cells in patients with emphysema. The molecular function of S100A8 was determined by an analysis of the oxidation status of its cysteine residues using chemoselective probes. Decreased S100A8 sulfination was observed in emphysema patients. In addition, its lower levels correlated with higher cell apoptosis induced by cigarette smoke extract in vitro. Cysteine at position 106 within DJ-1 is a central redox-sensitive residue. DJ-1 C106A mutant construct abolished the cytoprotective activity of DJ-1 against cell injury induced by cigarette smoke extract. Furthermore, a molecular and complementary relationship between DJ-1 and S100A8 was detected using gain- and loss-of-function studies. DJ-1 knockdown sensitized cells to apoptosis induced by cigarette smoke extract, and S100A8 overexpression provided cytoprotection in the absence of DJ-1. DJ-1 knockout mice were more susceptible to ATII cell apoptosis induced by cigarette smoke compared with wild-type mice. Our results indicate that the impairment of DJ-1 and S100A8 function may contribute to cigarette smoke-induced ATII cell injury and emphysema pathogenesis.


Assuntos
Células Epiteliais Alveolares/patologia , Apoptose , Calgranulina A/metabolismo , Proteína Desglicase DJ-1/metabolismo , Alvéolos Pulmonares/patologia , Enfisema Pulmonar/patologia , Idoso , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Calgranulina A/genética , Citoproteção , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estresse Oxidativo , Proteína Desglicase DJ-1/genética , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Fumaça/efeitos adversos
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