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Threshold of Biologic Response of the Small Airway Epithelium to Low Levels of Tobacco Smoke

ABSTRACT: Background: Healthy individuals exposed to low levels of cigarette smoke have a decrement in lung function and higher risk for lung disease compared to unexposed individuals. We hypothesized that healthy individuals exposed to low levels of tobacco smoke must have biologic changes in the small airway epithelium compared to healthy unexposed individuals. Methods: Small airway epithelium was obtained by bronchoscopy from 121 individuals; microarrays assessed genome wide gene expression, and urine nicotine and cotinine were used to categorized subjects as “nonsmokers,” “active smokers,” and “low exposure.” The gene expression data was used to determine the threshold and ID50 of urine nicotine and cotinine at which the small airway epithelium showed abnormal responses. Results: There was no threshold of urine nicotine without an abnormal small airway epithelial response, and only a slightly above detectable threshold abnormal response for cotinine. The nicotine ID50 for nicotine was 25 ng/ml and cotinine 104 ng/ml. Conclusions: The small airway epithelium detects and responds to low levels of tobacco smoke with transcriptome modifications. This provides biologic correlates of epidemiologic studies linking low level tobacco smoke exposure to lung health risk, health, identifies genes in the lung cells most sensitive to tobacco smoke and defines thresholds at the lung epithelium responds to inhaled tobacco smoke.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19667 | GEO | 2011/02/02

SECONDARY ACCESSION(S): PRJNA122485

REPOSITORIES: GEO

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Threshold of Biologic Response of the Small Airway Epithelium to Low Levels of Tobacco Smoke

Project description:Background: Healthy individuals exposed to low levels of cigarette smoke have a decrement in lung function and higher risk for lung disease compared to unexposed individuals. We hypothesized that healthy individuals exposed to low levels of tobacco smoke must have biologic changes in the small airway epithelium compared to healthy unexposed individuals. Methods: Small airway epithelium was obtained by bronchoscopy from 121 individuals; microarrays assessed genome wide gene expression, and urine nicotine and cotinine were used to categorized subjects as “nonsmokers,” “active smokers,” and “low exposure.” The gene expression data was used to determine the threshold and ID50 of urine nicotine and cotinine at which the small airway epithelium showed abnormal responses. Results: There was no threshold of urine nicotine without an abnormal small airway epithelial response, and only a slightly above detectable threshold abnormal response for cotinine. The nicotine ID50 for nicotine was 25 ng/ml and cotinine 104 ng/ml. Conclusions: The small airway epithelium detects and responds to low levels of tobacco smoke with transcriptome modifications. This provides biologic correlates of epidemiologic studies linking low level tobacco smoke exposure to lung health risk, health, identifies genes in the lung cells most sensitive to tobacco smoke and defines thresholds at the lung epithelium responds to inhaled tobacco smoke. Affymetrix arrays were used to assess the gene expression data of smoking-responsive genes in the in small airway epithelium obtained by fiberoptic bronchoscopy of 48 healthy non-smokers (non-smoker or Nsaets), 65 healthy smokers (smoker), 7 symptomatic smokers (SYMs) and a healthy occasional smoker (OcSs). YSB and LO contributed equally to the study.

2011-02-02 | E-GEOD-19667 | biostudies-arrayexpress

Persistence of Smoking-induced Dysregulation of Small Airway Epithelium miRNA Expression Despite Smoking Cessation

Project description:Rationale: Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to never-smokers. Objectives: Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. Methods: SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 10 healthy never-smokers and 10 healthy smokers, before and after they quit for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. Results: There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy never-smokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/Î²-catenin signaling pathway the top enriched pathway of the target genes of the persistent deregulated miRNAs. Conclusions: In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammation diseases or lung cancer, it is likely that persistent smoking-related changes in small airway epithelium miRNAs play a role in the subsequent development of these disorders. MicroRNA profiling identified 34 miRNAs up-regulated by cigarette smoking in human small airway epithelium. Even after quitting smoking for 3 months, 12 miRNAs didnât return to normal level.

2015-11-23 | E-GEOD-53519 | biostudies-arrayexpress

An application of a systems toxicology approach using a human organotypic small airway cultures for a comparative assessment between a candidate modified-risk tobacco product aerosol and cigarette smoke.

Project description:Along the trachea-bronchial tree, including the small airway region, cigarette smoke exposure induces inflammation, which can exacerbate the development of chronic obstructive pulmonary disease (COPD). The small airway region is known as the primary location of airway blockage in COPD and asthma. Therefore, evaluating exposure impact on the small airway is relevant for risk assessment. Using an in vitro human small airway culture model and a Systems Toxicology approach, this present study reports an assessment of the biological impact of an aerosol from a candidate modified-risk tobacco product, tobacco heating system (THS) 2.2, as compared with 3R4F smoke, at similar nicotine concentratng other functional measures (e.g., cytotoxicity, ciliary beating function, secretion of pro-inflammatory mediators) and histological assessment. The NPA methodology provides not only a qualitative measure of the exposure impact, but also a quantification of the exposure effect: the highest biological impact was observed in cultures 4 h post-exposure to 3R4F smoke at 0.15 mg nicotine/L (100% impact). In contrast, THS2.2 aerosol at similar nicotine concentration, only elicited 15% relative biological impact at 4 h post-exposure in the context of various biological processes modeled in the networks: Cell Fate, Cell Proliferation, Cell Stress, and Inflammatory Process Networks. Consistently, ciliary beating function and culture morphology were not remarkably altered in samples exposed to THS2.2 aerosol, even at nicotine concentration three times that of 3R4F smoke.

2017-10-26 | E-MTAB-6004 | biostudies-arrayexpress

Project description:Along the trachea-bronchial tree, including the small airway region, cigarette smoke exposure induces inflammation, which can exacerbate the development of chronic obstructive pulmonary disease (COPD). The small airway region is known as the primary location of airway blockage in COPD and asthma. Therefore, evaluating exposure impact on the small airway is relevant for risk assessment. Using an in vitro human small airway culture model and a Systems Toxicology approach, this present study reports an assessment of the biological impact of an aerosol from a candidate modified-risk tobacco product, tobacco heating system (THS) 2.2, as compared with 3R4F smoke, at similar nicotine concentrating other functional measures (e.g., cytotoxicity, ciliary beating function, secretion of pro-inflammatory mediators) and histological assessment. The NPA methodology provides not only a qualitative measure of the exposure impact, but also a quantification of the exposure effect: the highest biological impact was observed in cultures 4 h post-exposure to 3R4F smoke at 0.15 mg nicotine/L (100% impact). In contrast, THS2.2 aerosol at similar nicotine concentration, only elicited 15% relative biological impact at 4 h post-exposure in the context of various biological processes modeled in the networks: Cell Fate, Cell Proliferation, Cell Stress, and Inflammatory Process Networks. Consistently, ciliary beating function and culture morphology were not remarkably altered in samples exposed to THS2.2 aerosol, even at nicotine concentration three times that of 3R4F smoke.

2017-10-26 | E-MTAB-6098 | biostudies-arrayexpress

Persistence of Smoking-induced Dysregulation of Small Airway Epithelium miRNA Expression Despite Smoking Cessation

Project description:Rationale: Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to never-smokers. Objectives: Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. Methods: SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 10 healthy never-smokers and 10 healthy smokers, before and after they quit for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. Results: There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy never-smokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway the top enriched pathway of the target genes of the persistent deregulated miRNAs. Conclusions: In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammation diseases or lung cancer, it is likely that persistent smoking-related changes in small airway epithelium miRNAs play a role in the subsequent development of these disorders.

2015-11-23 | GSE53519 | GEO

Homo sapiens

Project description:Threshold of Biologic Response of the Small Airway Epithelium to Low Levels of Tobacco Smoke

| PRJNA122485 | ENA

Comparative biological impacts of an aerosol from carbon-heated tobacco and smoke from cigarettes on human respiratory epithelial cultures: A systems toxicology assessment (small airway epithelial cells-mRNA dataset)

Project description:The biological impact of an aerosol of a potential modified-risk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a systems toxicology approach. The potentially reduced effects of CHTP1.2 aerosol exposure were benchmarked against those of 3R4F cigarette smoke at similar nicotine concentrations. Experimental repetitions were conducted for which new batches of small airway and nasal cultures were exposed to CHTP1.2 aerosol or 3R4F smoke for 28 minutes. The biological impacts were determined based on a collection of endpoints including morphology, cytotoxicity, proinflammatory mediator profiles, cytochrome P450 1A1/1B1 activity, global mRNA and microRNA changes and proteome profiles. Alterations in mRNA expression were detected in cultures exposed to CHTP1.2 aerosol, without noticeable morphological changes and cytotoxicity, and minimal impact on proinflammatory mediator and proteome profiles. The changes linked to CHTP1.2 aerosol exposure, when observed, were transient. However, the impact of 3R4F smoke exposure persisted long post-exposure and greater than CHTP1.2 aerosol. Morphological changes were observed only in cultures exposed to 3R4F smoke. The lower biological effects of CHTP1.2 aerosol than 3R4F smoke exposure were observed similarly in both small airway and nasal epithelial cultures.

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2018-01-04 | E-MTAB-6608 | biostudies-arrayexpress

2018-01-04 | E-MTAB-6611 | biostudies-arrayexpress