Integration of transcriptome analysis with pathophysiological endpoints to evaluate cigarette smoke toxicity in an in vitro human airway tissue model

Autor: Rui Xiong, Levan Muskhelishvili, Tao Chen, Yue Wu, Qiangen Wu, Xuefei Cao, Priya Tripathi, Hans Rosenfeldt, Kelly Davis, Matthew Bryant, Sheila M Healy, Ying Chen
Rok vydání: 2021
Předmět:
0301 basic medicine
Lung Neoplasms
Health
Toxicology and Mutagenesis
Chronic obstructive pulmonary disease (COPD)
Bronchi
Toxicology
medicine.disease_cause
Organ Toxicity and Mechanisms
Pathogenesis
Transcriptome
Pulmonary Disease
Chronic Obstructive
03 medical and health sciences
0302 clinical medicine
Smoke
Tobacco
Toxicity Tests
Animals
Humans
Medicine
Respiratory system
Lung cancer
Lung
Cells
Cultured
Transcriptomic profiling
COPD
business.industry
Gene Expression Profiling
Smoking
Mucin
Air–liquid-interface (ALI) airway tissue model
Epithelial Cells
Pathophysiologically relevant endpoints
General Medicine
medicine.disease
Oxidative Stress
030104 developmental biology
030228 respiratory system
Toxicity
Immunology
Cytokines
Tobacco Smoke Pollution
business
Oxidative stress
Cigarette smoke (CS)
Zdroj: Archives of Toxicology
ISSN: 1432-0738
0340-5761
DOI: 10.1007/s00204-021-03008-0
Popis: Exposure to cigarette smoke (CS) is a known risk factor in the pathogenesis of smoking-caused diseases, such as chronic obstructive pulmonary diseases (COPD) and lung cancer. To assess the effects of CS on the function and phenotype of airway epithelial cells, we developed a novel repeated treatment protocol and comprehensively evaluated the progression of key molecular, functional, and structural abnormalities induced by CS in a human in vitro air–liquid-interface (ALI) airway tissue model. Cultures were exposed to CS (diluted with 0.5 L/min, 1.0 L/min, and 4.0 L/min clean air) generated from smoking five 3R4F University of Kentucky reference cigarettes under the International Organization for Standardization (ISO) machine smoking regimen, every other day for 4 weeks (3 days per week, 40 min/day). By integrating the transcriptomics-based approach with the in vitro pathophysiological measurements, we demonstrated CS-mediated effects on oxidative stress, pro-inflammatory cytokines and matrix metalloproteinases (MMPs), ciliary function, expression and secretion of mucins, and squamous cell differentiation that are highly consistent with abnormalities observed in airways of smokers. Enrichment analysis on the transcriptomic profiles of the ALI cultures revealed key molecular pathways, such as xenobiotic metabolism, oxidative stress, and inflammatory responses that were perturbed in response to CS exposure. These responses, in turn, may trigger aberrant tissue remodeling, eventually leading to the onset of respiratory diseases. Furthermore, changes of a panel of genes known to be disturbed in smokers with COPD were successfully reproduced in the ALI cultures exposed to CS. In summary, findings from this study suggest that such an integrative approach may be a useful tool for identifying genes and adverse cellular events caused by inhaled toxicants, like CS. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03008-0.
Databáze: OpenAIRE
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