From blood to lung tissue: effect of cigarette smoke on DNA methylation and lung function

Abstract Background Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

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Dynamic evolution of emphysema and airway remodeling in two mouse models of COPD

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01456-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yue Yang ◽

Tingting Di ◽

Zixiao Zhang ◽

Jiaxin Liu ◽

Congli Fu ◽

...

Keyword(s):

Lung Function ◽

Mouse Models ◽

Lung Tissue ◽

Airway Remodeling ◽

Exposed Group ◽

The Body ◽

Mouse Lung ◽

Control Group ◽

Suitable Model ◽

Exposure Method

Abstract Background Establishment of a mouse model is important for investigating the mechanism of chronic obstructive pulmonary disease (COPD). In this study, we observed and compared the evolution of the pathology in two mouse models of COPD induced by cigarette smoke (CS) exposure alone or in combination with lipopolysaccharide (LPS). Methods One hundred eight wild-type C57BL/6 mice were equally divided into three groups: the (1) control group, (2) CS-exposed group (CS group), and (3) CS + LPS-exposed group (CS + LPS group). The body weight of the mice was recorded, and noninvasive lung function tests were performed monthly. Inflammation was evaluated by counting the number of inflammatory cells in bronchoalveolar lavage fluid and measuring the expression of the IL-6 mRNA in mouse lung tissue. Changes in pathology were assessed by performing hematoxylin and eosin and Masson staining of lung tissue sections. Results The two treatments induced emphysema and airway remodeling and decreased lung function. Emphysema was induced after 1 month of exposure to CS or CS + LPS, while airway remodeling was induced after 2 months of exposure to CS + LPS and 3 months of exposure to CS. Moreover, the mice in the CS + LPS group exhibited more severe inflammation and airway remodeling than the mice in the CS group, but the two treatments induced similar levels of emphysema. Conclusion Compared with the single CS exposure method, the CS + LPS exposure method is a more suitable model of COPD in airway remodeling research. Conversely, the CS exposure method is a more suitable model of COPD for emphysema research due to its simple operation.

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DNA methylation is associated with airflow obstruction in patients living with HIV

Thorax ◽

10.1136/thoraxjnl-2020-215866 ◽

2020 ◽

pp. thoraxjnl-2020-215866

Author(s):

Ana I Hernandez Cordero ◽

Chen Xi Yang ◽

Maen Obeidat ◽

Julia Yang ◽

Julie MacIsaac ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Viral Infections ◽

Airflow Obstruction ◽

Normal Lung ◽

People Living With Hiv ◽

Global Methylation ◽

Age Related ◽

Impaired Lung Function ◽

Living With Hiv

IntroductionPeople living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.MethodsUsing blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1 decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.ResultsAirflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1 and FEV1/FVC, respectively. No positions were associated with FEV1 decline.ConclusionA large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.

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Transcriptomic Analysis of Lung Tissue from Cigarette Smoke–Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2016-0328oc ◽

2017 ◽

Vol 57 (1) ◽

pp. 47-58 ◽

Cited By ~ 22

Author(s):

Jeong H. Yun ◽

Jarrett Morrow ◽

Caroline A. Owen ◽

Weiliang Qiu ◽

Kimberly Glass ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Lung Tissue ◽

Transcriptomic Analysis ◽

Chronic Obstructive ◽

Murine Models ◽

Obstructive Pulmonary Disease

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Gene expression profiling of epigenetic chromatin modification enzymes and histone marks by cigarette smoke: implications for COPD and lung cancer

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00253.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. L1245-L1258 ◽

Cited By ~ 19

Author(s):

Isaac K. Sundar ◽

Irfan Rahman

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoke ◽

Histone Modifications ◽

Expression Patterns ◽

Chromatin Modification ◽

Gene Expression Patterns ◽

Validation Data ◽

Histone Marks

Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and histones, and for modulation of gene expression patterns in response to cigarette smoke (CS), are not known. We hypothesize that CS exposure alters the gene expression patterns of chromatin-modifying enzymes, which then affects multiple downstream pathways involved in the response to CS. We have, therefore, analyzed chromatin-modifying enzyme profiles and validated by quantitative real-time PCR (qPCR). We also performed immunoblot analysis of targeted histone marks in C57BL/6J mice exposed to acute and subchronic CS, and of lungs from nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). We found a significant increase in expression of several chromatin modification enzymes, including DNA methyltransferases, histone acetyltransferases, histone methyltransferases, and SET domain proteins, histone kinases, and ubiquitinases. Our qPCR validation data revealed a significant downregulation of Dnmt1, Dnmt3a, Dnmt3b, Hdac2, Hdac4, Hat1, Prmt1, and Aurkb. We identified targeted chromatin histone marks (H3K56ac and H4K12ac), which are induced by CS. Thus CS-induced genotoxic stress differentially affects the expression of epigenetic modulators that regulate transcription of target genes via DNA methylation and site-specific histone modifications. This may have implications in devising epigenetic-based therapies for COPD and lung cancer.

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Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure

10.1101/750638 ◽

2019 ◽

Author(s):

Patrick J Murphy ◽

Jingtao Guo ◽

Timothy G Jenkins ◽

Emma R James ◽

John R Hoidal ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Dna Methylation ◽

Cigarette Smoke ◽

Cigarette Smoke Exposure ◽

Epigenetic Changes ◽

Sperm Dna ◽

Increased Risk ◽

Paternal Smoking ◽

Sperm Dna Methylation

SUMMARYPaternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. This study used mouse models to evaluate: 1) what impact paternal CS exposure has on sperm DNA methylation (DNAme), 2) whether sperm DNAme changes persist after CS exposure ends, 3) the degree to which DNAme and gene expression changes occur in offspring and 4) the mechanism underlying impacts of CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking causes changes in neural DNAme and gene expression in offspring. Remarkably, the effects of CS exposure are largely recapitulated in oxidative stress-compromised Nrf2-/- mice and their offspring, independent of paternal smoking. These results demonstrate that paternal CS exposure impacts offspring phenotype and that oxidative stress underlies CS induced heritable epigenetic changes.

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Smoking, DNA methylation and lung function: a Mendelian randomization analysis to investigate causal relationships

10.1101/19003335 ◽

2019 ◽

Author(s):

Emily Jamieson ◽

Roxanna Korologou-Linden ◽

Robyn E. Wootton ◽

Anna L. Guyatt ◽

Thomas Battram ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Mendelian Randomization ◽

Causal Effect ◽

Forced Expiratory Volume ◽

Multiple Trait ◽

Genome Wide ◽

Causal Variants ◽

Association Data ◽

Randomization Analysis

AbstractWhether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in one second (FEV1) in two-sample Mendelian randomization (MR) using methylation quantitative trait loci and genome-wide association data for FEV1. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p<1.2×10−4). Replication analysis supported a causal effect at three CpGs (cg21201401 (ZGPAT), cg19758448 (PGAP3) and cg12616487 (AHNAK) (p<0.0028). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites may influence lung function via effects on smoking. Using multiple-trait colocalization, we found evidence of shared causal variants between lung function, gene expression and DNA methylation. Findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although large, tissue-specific datasets are required to confirm these results.

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Long-term PM2.5 Exposure, Genome-wide DNA Methylation and Lung Function in Korean Adults

10.1109/bibm52615.2021.9669818 ◽

2021 ◽

Author(s):

Ye-Eun Han ◽

Nak-Hyeon Choi ◽

Mi Jin Cho ◽

Min Gu Kang ◽

Young-Youl Kim

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Korean Adults ◽

Genome Wide ◽

Pm2.5 Exposure

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Smoking and Asthma

PEDIATRICS ◽

10.1542/peds.76.4.655 ◽

1985 ◽

Vol 76 (4) ◽

pp. 655-655

Author(s):

FRANK PEDREIRA

Keyword(s):

Lung Function ◽

Cigarette Smoking ◽

Cigarette Smoke ◽

Tobacco Smoke ◽

Clinical Impression ◽

Children With Asthma

In Reply.— We thank Dr Berkowitz for his thoughtful response to our paper in the March 1985 issue of Pediatrics. Our study was not designed to address the problem of smoking effect on asthma. However, a number of investigations have shown that atopic individuals may develop wheezing after exposure to tobacco smoke.1-4 Moreover, several studies have demonstrated that cigarette smoke can cause bronchoconstriction and associated decrease in lung function.5-7 These studies support the clinical impression of Dr Berkowitz that children with asthma will "have less problems if their parents stop or decrease their amount of cigarette smoking."

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