Site and Nature of Airway Obstruction in Chronic Obstructive Lung Disease

Hogg, James C.; Macklem, Peter T.; Thurlbeck, William M.

doi:10.1056/nejm196806202782501

Cited by 1,201 publications

(745 citation statements)

References 14 publications

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“…The present study adds to this concept, demonstrating that chronic insult to the lung by cigarette smoking is associated with significant changes in methylation patterns of the DNA derived from the SAE, the epithelial population that demonstrates the first evidence of smoking-induced pathology, and the initial site of development of most smoking-related lung disorders (30)(31)(32). We assayed these DNA methylation changes using the HELP assay, which relies on the use of methylation-sensitive and -insensitive restriction enzymes; therefore, only CpGs that are recognized by the restriction enzymes will be assayed.…”

Section: Discussionmentioning

confidence: 69%

“…With this background, we hypothesized that cigarette smoke, with its .4000 compounds and 10 14 oxidants per puff, may have profound effects on the methylome of the small airway epithelium (SAE), the cell population that takes the initial stress of cigarette smoke and is the first site of lung pathology in cigarette smokers (26)(27)(28)(29)(30)(31)(32). In humans, the SAE consists of four major cell types: ciliated, secretory, columnar and basal cells (30,33).…”

Section: Introductionmentioning

confidence: 99%

“…Cigarette smoking is associated with disordering of the differentiation of the SAE basal cells, with consequent disordered function of the airway mucociliary barrier (34,35). The ability of the SAE to alter gene expression in response to external stimuli is critical to airway defense and repair mechanisms (30,31,34,36).…”

Section: Introductionmentioning

confidence: 99%

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Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Buro-Auriemma

Salit

Hackett

et al. 2013

Human Molecular Genetics

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The small airway epithelium (SAE), the first site of smoking-induced lung pathology, exhibits genome-wide changes in gene expression in response to cigarette smoking. Based on the increasing evidence that the epigenome can respond to external stimuli in a rapid manner, we assessed the SAE of smokers for genome-wide DNA methylation changes compared with nonsmokers, and whether changes in SAE DNA methylation were linked to the transcriptional output of these cells. Using genome-wide methylation analysis of SAE DNA of nonsmokers and smokers, the data identified 204 unique genes differentially methylated in SAE DNA of smokers compared with nonsmokers, with 67% of the regions with differential methylation occurring within 2 kb of the transcriptional start site. Among the genes with differential methylation were those related to metabolism, transcription, signal transduction and transport. For the differentially methylated genes, 35 exhibited a correlation with gene expression, 54% with an inverse correlation of DNA methylation with gene expression and 46% a direct correlation. These observations provide evidence that cigarette smoking alters the DNA methylation patterning of the SAE and that, for some genes, these changes are associated with the smoking-related changes in gene expression.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Buro-Auriemma

Salit

Hackett

et al. 2013

Human Molecular Genetics

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“…The major histopathologic correlates of airway obstruction in COPD are loss of alveolar walls and narrowing of the small airways (3). The relative contribution of each of these pathologic features to airway obstruction is not completely understood (4).…”

Section: Introductionmentioning

confidence: 99%

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Araya¹,

Cambier²,

Markovics³

et al. 2007

J. Clin. Invest.

230

228

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Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin α v β 8 , which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

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“…Us e f u l P h y s i c a l S i g n s f o r Di a g n o s i s o f COP D the contrary, hypertrophy of scalenus muscles is more likely identified in patients with restrictive lung disease (6).…”

Section: Chronic Obstructive Pulmonary Disease (Copd) Is a Major Globmentioning

confidence: 97%

Physical Diagnosis of Chronic Obstructive Pulmonary Disease

Tokuda

Miyagi²

2007

Intern. Med.

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Site and Nature of Airway Obstruction in Chronic Obstructive Lung Disease

Cited by 1,201 publications

References 14 publications

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Physical Diagnosis of Chronic Obstructive Pulmonary Disease

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