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2.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3660-3671, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402290

RESUMO

To study the effect of anemoside B4 on rats with chronic obstructive pulmonary disease (COPD).Seventy-two SD male rats were randomly divided into blank group and model group.The method of exposure to cigarette smoke and combined with lipopolysaccharide (LPS) was used to replicate the rat model of COPD.After the model was maintained for 5 weeks,the rats were randomly divided into model group,dexamethasone group (0.81 mg·kg~(-1)) and anemoside B4 low,medium and high (2,4,8 mg·kg~(-1)) dose groups,a group of 12 animals were administered,and then the administration was started.The administration was maintained until the28th day,and the pulmonary function parameters of rats were measured by an animal pulmonary function instrument.After testing the rat lung function parameters,immediately draw rat alveolar lavage fluid (BALF),and use high-throughput protein chip technology to determined the expression levels of inflammatory cytokines in rat BALF.HE staining was used to observe the general pathological changes of rat lung and tracheal tissue.Masson staining was used to observe the collagen deposition in rat lung tissue.Real-time q PCR method was used to determine the mRNA expression level of related genes in rat lung tissue.Western blot method was used to determine the expression levels of related proteins in rat lung tissues.According to the findings,compared with the model group,the dexamethasone group and the anemoside B4 drug groups had different degrees of increase in the lung function parameters of rats (P<0.01,P<0.05),improved the expression level of inflammatory cytokines in the BALF of rats to varying degrees (P<0.01,P<0.05),and improved the pathological structure of rat lung tissue to varying degrees.Relative mRNA expressions of matrix metalloproteinase 2 (MMP-2),matrix metalloproteinase 12 (MMP-12),matrix metalloproteinase inhibitor 1 (TIMP-1),interleukin-6 (IL-6),and transforming growth factor-ß1 (TGF-ß1) were significantly reduced (P<0.01);whereas relative mRNA expressions of matrix metalloproteinase 9(MMP-9) and matrix metalloproteinase inhibitor 2 (TIMP-2) were increased significantly (P<0.01).The mRNA and protein expression levels of T-box transcription factor (T-bet),interleukin-12 (IL-12) and signal transducer and activator of transcription 4(STAT4) reduced to varying degrees (P<0.01,P<0.05).The mRNA of transcription factor GATA3 (binding protein-3),interleukin-4 (IL-4) and signal transducer and activator of transcription 6 (STAT6) in rat lung tissues and the protein expression levels of IL-4 and STAT6 were increased to varying degrees (P<0.01,P<0.05).In conclusion,anemoside B4 has a certain protective effect on COPD rats caused by cigarette smoke exposure and combined with LPS.The mechanism of action may be related to the regulation of IL-12/STAT4 and IL-4/STAT6 signaling pathways.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Fator de Transcrição STAT4 , Animais , Interleucina-12 , Interleucina-4 , Pulmão/metabolismo , Masculino , Metaloproteinase 2 da Matriz , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Ratos , Fator de Transcrição STAT4/metabolismo , Fator de Transcrição STAT6/metabolismo , Saponinas
3.
Int J Chron Obstruct Pulmon Dis ; 16: 2351-2362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34429593

RESUMO

Purpose: This study aimed to identify the COPD molecular subtypes reflecting pulmonary function damage on the basis of metabolism-related gene expression, which provided the opportunity to study the metabolic heterogeneity and the association of metabolic pathways with pulmonary function damage. Methods: Univariate linear regression and the Boruta algorithm were used to select metabolism-related genes associated with forced expiratory volume in the first second (FEV1) and FEV1/forced vital capacity (FVC) in the Evaluation of COPD to Longitudinally Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. COPD subtypes were further identified by consensus clustering with best-fit. Then, we analyzed the differences in the clinical characteristics, metabolic pathways, immune cell characteristics, and transcription features among the subtypes. Results: This study identified two subtypes (C1 and C2). C1 exhibited higher levels of lower pulmonary function and innate immunity than C2. Ten metabolic pathways were confirmed as key metabolic pathways. The pathways related to N-glycan, hexosamine, purine, alanine, aspartate and glutamate tended to be positively associated with the abundance of adaptive immune cells and negatively associated with the abundance of innate immune cells. In addition, other pathways had opposite trends. All results were verified in Genetic Epidemiology of COPD (COPDGene) datasets. Conclusion: The two subtypes reflect the pulmonary function damage and help to further understand the metabolic mechanism of pulmonary function in COPD. Further studies are needed to prove the prognostic and therapeutic value of the subtypes.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Volume Expiratório Forçado , Humanos , Pulmão , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Testes de Função Respiratória , Capacidade Vital
4.
Genes (Basel) ; 12(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356070

RESUMO

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin-angiotensin-aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Asma/diagnóstico , Teste para COVID-19 , COVID-19/enzimologia , Hipertensão Pulmonar/diagnóstico , Pulmão/enzimologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Asma/enzimologia , Asma/genética , COVID-19/genética , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Inflamação/diagnóstico , Inflamação/enzimologia , Inflamação/genética , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/genética , Sistema Renina-Angiotensina
5.
Redox Biol ; 45: 102055, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34214709

RESUMO

BACKGROUND: Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are linked to several mitochondrial alterations. Cigarette smoke (CS) alters the structure and function of mitochondria. OPA1 is the main inner mitochondrial GTPase responsible for the fusion events. OPA1 undergoes proteolytic cleavage from long to short forms during acute stress and mitophagy. However, the exact role of OPA1 isoforms and related proteins during CS-induced mitophagy and COPD is not clear. METHODS: Lung tissues from non-smokers, smokers, COPD and IPF were used to determine the relative expression of OPA1 and related proteins. Additionally, we used mouse lungs from chronic (6 months) CS exposure to evaluate the status of OPA1. Primary lung fibroblasts from normal and COPD patients and naked mole rat (NMR) lung fibroblasts, human fetal lung fibroblast (HFL1), mouse embryonic fibroblast from wild type (WT), OPA1-/-, MFN1 and MFN2-/- were used to determine the effect of CS on OPA1 isoforms. Various mitochondrial fusion promoters/activators (BGP-15, leflunomide, M1) and fission inhibitor (DRP1) were used to determine their effect on OPA1 status and cigarette smoke extract (CSE)-induced lung epithelial (BEAS2B) cell damage, respectively. Seahorse flux analyzer was used to determine the effect of these compounds in BEAS2B cells with and without CSE exposure. FINDINGS: Short OPA1 isoforms were predominantly detected and significantly increased in COPD subjects. Acute CSE treatment in various cell lines except NMR was found to increase the conversion of long to short OPA1 isoforms. CSE treatment significantly increased mitochondrial stress-related protein SLP2 in all the cells used. OPA1 interacting partners like prohibitins (PHB1 and 2) were also altered depending on the CS exposure. Finally, BGP-15 and leflunomide treatment were able to preserve the long OPA1 isoform in cells treated with CSE. INTERPRETATION/CONCLUSION: The long OPA1 isoform along with SLP2 and prohibitins play a crucial role in CS-induced lung damage, causing mitophagy/mitochondrial dysfunction in COPD, which may be used as a novel therapeutic target in COPD.


Assuntos
Proteínas Mitocondriais , Doença Pulmonar Obstrutiva Crônica , Animais , Fibroblastos , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Pulmão/metabolismo , Camundongos , Mitocôndrias , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça/efeitos adversos , Tabaco , Fumar Tabaco
6.
Int J Chron Obstruct Pulmon Dis ; 16: 2105-2118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295155

RESUMO

Background: Emerging evidence has reported that circular RNAs (circRNAs) are aberrantly expressed and act as significant regulators in pathological processes of chronic obstructive pulmonary disease (COPD). Here, the purpose of this article was to evaluate and clarify the biological functions and mechanism of circRNA single stranded interacting protein 1 (circ-RBMS1) in cigarette smoke (CS)-induced COPD. Methods: Human bronchial epithelial cells 16HBE treated with or without cigarette smoke extract (CSE) were used in the experimental group in vitro. Levels of circ-RBMS1, microRNA (miR)-197-3p, and F-box only protein 11 (FBXO11) were detected using quantitative real-time polymerase chain reaction and Western blot. The present study used cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EDU), flow cytometry and Western blot assays to determine the survival of 16HBE cells. The activity of interleukin (IL)-1ß, tumor necrosis factor (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) was evaluated using the relative commercial kits. Dual-luciferase activity and RIP assays were used to identify the target relationship between miR-197-3p and circ-RBMS1 or FBXO11. Results: Circ-RBMS1 was highly expressed in COPD patients, and CSE induced an increased expression of circ-RBMS1 in a dose-dependent manner. Functionally, knockdown of circ-RBMS1 attenuated CSE-induced apoptosis, inflammation and oxidative stress in 16HBE cells. Circ-RBMS1 directly targeted miR-197-3p, and miR-197-3p inhibition reversed the effects of circ-RBMS1 knockdown on CSE-induced 16HBE cells. FBXO11 was a target of miR-197-3p. MiR-197-3p overexpression or FBXO11 silencing reduced the apoptosis, inflammation and oxidative stress in CSE-induced 16HBE cells. Moreover, miR-197-3p exerted its effects by targeting FBXO11. Additionally, circ-RBMS1 acted as a sponge for miR-197-3p to positively regulate FBXO11 expression in 16HBE cells. Conclusion: Circ-RBMS1 knockdown alleviated CSE-induced apoptosis, inflammation and oxidative stress in 16HBE cells via miR-197-3p/FBXO11 axis, suggesting a new insight into the pathogenesis of CS-induced COPD.


Assuntos
Proteínas F-Box , MicroRNAs , Doença Pulmonar Obstrutiva Crônica , RNA Circular/genética , Apoptose , Proteínas de Ligação a DNA , Técnicas de Silenciamento de Genes , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo , Proteína-Arginina N-Metiltransferases , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Ligação a RNA/genética
7.
Int J Chron Obstruct Pulmon Dis ; 16: 2165-2179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34321876

RESUMO

Purpose: The clinical and inflammatory associations of mast cells (MCs) and basophils in chronic obstructive pulmonary disease (COPD) are poorly understood. We previously developed and validated a qPCR-based MC/basophil gene signature in asthma to measure these cells in sputum samples. Here, we measured this gene signature in a COPD and control population to explore the relationship of sputum MCs/basophils to inflammatory and COPD clinical characteristics. Patients and Methods: MC/basophil signature genes (TPSAB1/TPSB2, CPA3, ENO2, GATA2, KIT, GPR56, HDC, SOCS2) were measured by qPCR in sputum from a COPD (n=96) and a non-respiratory control (n=17) population. Comparative analyses of gene expression between the COPD and the control population, and between eosinophilic COPD and non-eosinophilic COPD were tested. Logistic regression analysis and Spearman correlation were used to determine relationships of sputum MC/basophil genes to inflammatory (sputum eosinophil proportions, blood eosinophils) and clinical (age, body mass index, quality of life, lung function, past year exacerbations) characteristics of COPD. Results: MC/basophil genes were increased in COPD versus control participants (CPA3, KIT, GATA2, HDC) and between eosinophilic-COPD and non-eosinophilic COPD (TPSB2, CPA3, HDC, SOCS2). We found all MC/basophil genes were positively intercorrelated. In COPD, MC/basophil genes were associated with eosinophilic airway inflammation (GATA2, TPSB2, CPA3, GPR56, HDC, SOCS2), blood eosinophilia (all genes) and decreased lung function (KIT, GATA2, GPR56, HDC). Conclusion: We demonstrate associations of MCs and basophils with eosinophilic inflammation and lower lung function in COPD. These findings are consistent with prior results in asthma and may represent a new tool for endotyping eosinophilic-COPD.


Assuntos
Basófilos , Doença Pulmonar Obstrutiva Crônica , Eosinófilos , Expressão Gênica , Humanos , Mastócitos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Qualidade de Vida , Escarro
8.
Free Radic Biol Med ; 172: 541-549, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34224814

RESUMO

Airway epithelial mitochondrial oxidative stress and damage is an important pathology in chronic obstructive pulmonary disease (COPD). Mitophagy involves MAPK15-ULK1 signaling, the role of which is unknown in COPD. This study investigated MAPK15-ULK1 signaling in airway epithelial cells of COPD patients and its activation by cigarette smoke extract (CSE) in isolated human airway epithelial cells. Significant increased phosphorylation of MAPK15 and ULK1 (Ser555) was detected in the airway epithelium of COPD patients. This pathology was maintained in isolated primary COPD-epithelial cells. Compared to control cells, the protein expression of Beclin1 and the ratio of LC3II to LC3I were both significantly increased in COPD-epithelial cells. In human airway epithelial cells, CSE significantly increased the phosphorylation of MAPK15, ULK1 (Ser555), the expression of Beclin1, and the LC3II/LC3I ratio in a concentration- and time-dependent manner. Transfection with MAPK15 siRNA significantly inhibited the CSE-induced ULK1 (Ser555) phosphorylation in airway epithelial cells. Silencing of MAPK15 or ULK1 significantly reduced CSE-induced mitophagy and mitochondrial oxidative stress, thereby improving cell viability. In summary, cigarette smoke activated MAPK15-ULK1 signaling, thereby promoting mitophagy and mitochondrial oxidative stress in airway epithelial cells. This signaling pathway is activated in COPD-epithelial cells and therefore might present a novel therapeutic target for COPD.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , MAP Quinases Reguladas por Sinal Extracelular , Peptídeos e Proteínas de Sinalização Intracelular , Mitofagia , Doença Pulmonar Obstrutiva Crônica , Transdução de Sinais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Células Epiteliais , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumaça
9.
Int J Chron Obstruct Pulmon Dis ; 16: 1535-1547, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103911

RESUMO

Background: Smoking is the most common cause of chronic obstructive pulmonary disease (COPD), and the early diagnosis for COPD remains poor. Exploring the molecular mechanism and finding feasible biomarkers will be beneficial for clinical management of COPD. Circular RNAs (circRNAs) are noncoding RNAs that act as miRNA sponges to regulate the expression levels of genes, leading to the changes of cellular phenotypes and disease progression. CircRNA HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (circ-HACE1) was abnormally expressed after the induction of cigarette smoke extract (CSE) in cell model. This study was performed to explore its function and mechanism in COPD. Methods: Circ-HACE1, microRNA-485-3p (miR-485-3p) and toll-like receptor 4 (TLR4) detection was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis/cell cycle were respectively examined using cell counting kit-8 (CCK-8) and flow cytometry. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Oxidative stress was evaluated through the measurement of malondialdehyde (MDA) and superoxide dismutase (SOD). The target binding analysis was conducted via dual-luciferase reporter assay. Western blot was employed for protein expression detection of TLR4. Results: Circ-HACE1 was overexpressed in smokers or smokers with COPD and CSE upregulated circ-HACE1 expression in 16HBE cells. Knockdown of circ-HACE1 attenuated CSE-stimulated cell viability and cell cycle repression, as well as the enhancement of cell apoptosis, inflammatory response and oxidative stress. MiR-485-3p was a target of circ-HACE1. Circ-HACE1 regulated CSE-induced cell injury via targeting miR-485-3p. TLR4 was a downstream target of miR-485-3p, and miR-485-3p inhibited the CSE-induced cell damages by directly downregulating the level of TLR4. Circ-HACE1/miR-485-3p regulated TLR4 expression in CSE-treated 16HBE cells, and TLR4 overexpression also reversed all effects of si-circ-HACE1 on CSE-treated 16HBE cells. Conclusion: These findings elucidated that circ-HACE1 contributed to the CSE-induced cell damages in COPD cell models via regulating TLR4 by acting as the sponge of miR-485-3p.


Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Células Epiteliais , Humanos , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/efeitos adversos , Receptor 4 Toll-Like/genética , Ubiquitina-Proteína Ligases
10.
Mutat Res Rev Mutat Res ; 787: 108344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083053

RESUMO

Respiratory tissues are highly susceptible to diseases due to the constant exposure to physical and chemical airborne pollutants. Chronic obstructive pulmonary disease (COPD) and lung cancer are among the most common causes of serious illness and death worldwide. The inflammatory environment associated with these respiratory diseases has long been accepted as the major player in the development of airway abnormalities. The presence and relevance of DNA damage and genomic instability makes the micronucleus assay a suitable candidate to quantitatively estimate these early pathogenetic events. A systematic review and meta-analysis were planned to determine underlying common mechanisms that can explain the relationships between COPD and lung cancer. A total of 17 studies from Jan 1999 to Dec 2019 comparing micronucleus frequency in patients affected by respiratory diseases vs healthy controls were analysed. Our results confirmed the presence of significant association between MN frequency and the diseases investigated, and suggested a circle of events linking inflammation induced oxidative stress to the risk of disease through genomic instability and hypoxia. Therefore, using non-invasive, robust and cost effective genomic instability assays such as the micronucleus assay, would allow us to capture unique phenotypic and biological changes that would allow the identification of subjects at high risk of developing lung diseases and improve early detection strategies.


Assuntos
Instabilidade Genômica/genética , Inflamação/genética , Neoplasias Pulmonares/genética , Testes para Micronúcleos/métodos , Doença Pulmonar Obstrutiva Crônica/genética , Animais , Humanos , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia
11.
Int J Chron Obstruct Pulmon Dis ; 16: 1621-1636, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113094

RESUMO

Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD). Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD. Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry. Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged. Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.


Assuntos
Fosfatidilinositol 3-Quinases , Doença Pulmonar Obstrutiva Crônica , Progressão da Doença , Volume Expiratório Forçado , Humanos , Fosfatidilinositol 3-Quinase , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Escarro
12.
FASEB J ; 35(7): e21300, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34165809

RESUMO

GPR126 is an adhesion G protein-coupled receptor which lies on chromosome 6q24. Genetic variants in this region are reproducibly associated with lung function and COPD in genome wide association studies (GWAS). The aims of this study were to define the role of GPR126 in the human lung and in pulmonary disease and identify possible casual variants. Online tools (GTEx and LDlink) identified SNPs which may have effects on GPR126 function/ expression, including missense variant Ser123Gly and an intronic variant that shows eQTL effects on GPR126 expression. GPR126 signaling via cAMP-mediated pathways was identified in human structural airway cells when activated with the tethered agonist, stachel. RNA-seq was used to identify downstream genes/ pathways affected by stachel-mediated GPR126 activation in human airway smooth muscle cells. We identified ~350 differentially expressed genes at 4 and 24 hours post stimulation with ~20% overlap. We identified that genes regulated by GPR126 activation include IL33, CTGF, and SERPINE1, which already have known roles in lung biology. Pathways altered by GPR126 included those involved in cell cycle progression and cell proliferation. Here, we suggest a role for GPR126 in airway remodeling.


Assuntos
Brônquios/fisiologia , Células Epiteliais/fisiologia , Músculo Liso/fisiologia , Mutação de Sentido Incorreto , Doença Pulmonar Obstrutiva Crônica/patologia , Receptores Acoplados a Proteínas G/genética , Sistema Respiratório/fisiopatologia , Brônquios/citologia , Proliferação de Células , Células Cultivadas , Células Epiteliais/citologia , Genômica , Humanos , Músculo Liso/citologia , Doença Pulmonar Obstrutiva Crônica/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
13.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063608

RESUMO

Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-ß-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis.


Assuntos
Senescência Celular/genética , Fumar Cigarros/efeitos adversos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Lesão Pulmonar/genética , Doença Pulmonar Obstrutiva Crônica/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Senescência Celular/efeitos dos fármacos , Fumar Cigarros/genética , Fumar Cigarros/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibronectinas/genética , Regulação da Expressão Gênica/genética , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Serpina E2/genética
14.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071592

RESUMO

Lung cancer remains the leading cause of cancer related mortality worldwide. We aimed to test whether a simple blood biomarker (extracellular vesicle miRNAs) can discriminate between cases with and without lung cancer. METHODS: plasma extracellular vesicles (EVs) were isolated from four cohorts (n = 20 in each): healthy non-smokers, healthy smokers, lung cancer, and stable COPD participants. EV miRNA expression was evaluated using the miRCURY LNA miRNA Serum/Plasma assay for 179 specific targets. Significantly dysregulated miRNAs were assessed for discriminatory power using ROC curve analysis. RESULTS: 15 miRNAs were differentially expressed between lung cancer and healthy non-smoking participants, with the greatest single miRNA being miR-205-5p (AUC 0.850), improving to AUC 0.993 in combination with miR-199a-5p. Moreover, 26 miRNAs were significantly dysregulated between lung cancer and healthy smoking participants, with the greatest single miRNA being miR-497-5p (AUC 0.873), improving to AUC 0.953 in combination with miR-22-5p; 14 miRNAs were significantly dysregulated between lung cancer and stable COPD participants, with the greatest single miRNA being miR-27a-3p (AUC 0.803), with two other miRNAs (miR-106b-3p and miR-361-5p) further improving discriminatory power (AUC 0.870). CONCLUSION: this case control study suggests miRNAs in EVs from plasma holds key biological information specific for lung cancer and warrants further prospective assessment.


Assuntos
Biomarcadores Tumorais/genética , Vesículas Extracelulares/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Idoso , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Curva ROC
15.
J Biol Regul Homeost Agents ; 35(3): 987-999, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159768

RESUMO

Chronic obstructive pulmonary disease (COPD) represents a chronic inflammatory disorder of the airways induced mainly by cigarette smoking. In the current study, cigarette smoke extract (CSE) was used to develop an in vitro COPD model using human bronchial epithelium (HBE) cells to expound the possible role of microRNA-29b (miR-29b) in COPD. Firstly, miR-29b and interleukin (IL)-22 expression was assessed in serum of 20 healthy non-smokers, 20 healthy smokers and 20 COPD patients as well as CSE-treated HBE cells. Then, miR-29b and IL-22 expression was altered to evaluate their functions in Th17/Treg ratio. miR-29b inhibited Th17/Treg ratio and levels of IL-22; whereas overexpression of IL-22 reversed these trends. Moreover, rescue experiments found that IL-22 neutralized the repressive effects of miR-29b on Th17/Treg ratio and inflammatory response. Finally, we found that miR-29b blocked the JAK/STAT3 pathway in CSE-treated HBE cells. These data highlighted that miR-29bs modulated Th17/Treg imbalance in CSE-induced experimental COPD through inhibition of IL-22-dependent JAK/STAT3 pathway.


Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Humanos , Interleucinas/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Linfócitos T Reguladores
16.
Int J Chron Obstruct Pulmon Dis ; 16: 1369-1379, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040365

RESUMO

Background: Chronic inflammation, oxidative stress, and apoptosis play critical roles in chronic obstructive pulmonary disease (COPD) pathogenesis. Here, we attempted to determine whether aerobic exercise (AE) could improve COPD by counteracting the COPD-associated inflammatory response, oxidative stress, and apoptosis in mice. Methods: Thirty male ICR mice were assigned into one of three groups: control (Con), COPD, and COPD + AE. COPD was simulated by intratracheal injection of lipopolysaccharide (LPS) for 4 weeks. Low-intensity AE was performed for 4 weeks. Bronchoalveolar lavage fluid (BALF) cell counts and the levels of inflammatory cytokine in BALF and serum were detected. Hematoxylin and eosin (HE), Masson trichrome, and Sirius Red staining as well as terminal deoxynucleotidyl transferase dUTP nick end labeling were performed to identify the degree of pulmonary emphysema, bronchial mucus cell hyperplasia, pulmonary fibrosis, and cell apoptosis. Oxidative stress parameters were measured. Furthermore, gene expression levels for the CXCL1, IL-1ß, IL-10, IL-17, matrix metalloproteinase (MMP)9, TGF-ß, TNF-α, and silent information regulator (sirt)1 were detected in mice lung tissues. Results: AE improved LPS-induced emphysema, pulmonary fibrosis, bronchial mucus cell hyperplasia, bronchoconstriction, and cell apoptosis. AE prevented an LPS-induced increase in the total cell, neutrophil, and macrophage counts. AE decreased malondialdehyde (MDA) and myeloperoxidase (MPO) levels but increased glutathione (GSH) and superoxide dismutase (SOD) levels. AE decreased BALF levels of IL-1ß, TNF-α, and TGF-ß but increased BALF IL-10 levels. AE suppressed the gene expression levels of pro-inflammatory factors CXCL1, IL-1ß, IL-17, and TNF-α and profibrotic factors MMP-9 and TGF-ß but activated those of anti-inflammatory factor IL-10 and lung-protective factor sirt1. Conclusion: AE is a potential therapeutic approach for COPD. AE improved emphysema, bronchial mucus cell hyperplasia, and pulmonary fibrosis in mice with COPD by alleviating the inflammatory response, oxidative stress injury, and cell apoptosis as well as activating sirt1.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Animais , Apoptose , Líquido da Lavagem Broncoalveolar , Inflamação/genética , Inflamação/prevenção & controle , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/terapia
17.
Respir Med ; 184: 106466, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34010739

RESUMO

Alpha1-antitrypsin deficiency arises due to mutations in alpha1-antitrypsin (AAT) gene and represents the most prominent genetic predisposition to chronic obstructive pulmonary disease and emphysema. Since AAT plays important immunomodulatory and tissue-protective roles and since it was suggested to protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed this association in United Kingdom Biobank, a community-based cohort with >500,000 participants. The most common, mild AATD genotypes were associated neither with increased SARS-CoV-2 infection rates nor with increased SARS-CoV-2 fatalities, while the numbers of severe AATD cases were too low to allow definitive conclusions.


Assuntos
COVID-19/prevenção & controle , Predisposição Genética para Doença/genética , Deficiência de alfa 1-Antitripsina/genética , Doença Aguda , COVID-19/epidemiologia , COVID-19/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Mutação , Resultados Negativos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/fisiologia , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Índice de Gravidade de Doença , Reino Unido/epidemiologia , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/fisiologia
19.
Respir Res ; 22(1): 164, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34051791

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). CONCLUSION: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.


Assuntos
COVID-19/genética , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Transcriptoma , Idoso , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Basigina/genética , Basigina/metabolismo , COVID-19/diagnóstico , COVID-19/metabolismo , COVID-19/fisiopatologia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Regulação da Expressão Gênica , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Capacidade Vital
20.
Zhen Ci Yan Jiu ; 46(4): 266-71, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33931989

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) and "Feishu" (BL13) on the expression of autophagy related proteins in the lung tissue of rats with chronic obstructive pulmonary disease (COPD), so as to explore the mechanism of EA underlying improvement of COPD. METHODS: Thirty male SD rats were randomly divided into normal, model and EA groups (n=10 in each group). The COPD model was established by intratracheal infusion of Lipopolysaccharide (LPS, 1 mg/kg) and exposure in cigarette smoke. EA was applied to bilateral ST36 and BL13 for 30 min, once every other day for 2 weeks. The pulmonary function (forced vital capacity ï¼»FVCï¼½, forced expiratory volume in 0.1 s and 0.3 s ï¼»FEV0.1, FEV0.3ï¼½, FEV0.1/FVC and FEV0.3/FVC) was detected by animal pulmonary function analysis system. Histopathological changes of the airway and lung were displayed by H.E. staining. Autophagosomes in the airway and lung tissues were observed by electron microscope. The expression of AMP activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Unc-51 like autophagy activating kinase 1(ULK1), autophagy related protein ATG6(Beclin1)mRNAs in lung tissue were examined by quantitative real-time PCR. The expression of AMPK, mTOR, ULK1, Beclin1 and microtubule-associated protein 1 light chain 3 (LC3)proteins in lung tissue were examined by Western blot. The contents of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in the broncho alveolar lavage fluid (BALF) were assayed by ELISA. RESULTS: Following modeling, the FVC, FEV0.1, FEV0.3, FEV0.1/FVC and FEV0.3/FVC levels were significantly decreased (P<0.01), the infiltration of inflammatory cells and the increase of autophagosomes were obvious in airway and lung tissue, the mRNA and protein expression of AMPK, ULK1, Beclin1 and the ratio of LC3Ⅱ/LC3Ⅰ were increased (P<0.01), while the mRNA and protein expression of mTOR were decreased (P<0.01), the contents of TNF-α and IL-6 in the BALF were increased in the model group compared with the normal group (P<0.01). After EA intervention, all the indexes mentioned above were completely reversed in the EA group relevant to the model group (P<0.01, P<0.05). CONCLUSION: EA at ST36 and BL13 can improve the lung function of COPD rats, which may be related to its effects in inhibiting the autophagy level and reducing the inflammation response in the lung.


Assuntos
Eletroacupuntura , Doença Pulmonar Obstrutiva Crônica , Animais , Proteínas Relacionadas à Autofagia , Pulmão , Masculino , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/terapia , Ratos , Ratos Sprague-Dawley
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