Characterizing hookah smoking-induced transcriptional regulations in the human bronchial epithelial cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162386 | GEO | 2024/01/31
REPOSITORIES: GEO
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Project description:As part of current harm reduction strategies, candidate modified risk tobacco products (MRTP) are developed to offer adult smokers who want to continue using tobacco product an alternative to cigarettes while potentially reducing individual risk and population harm compared to smoking cigarettes. One of these candidate MRTPs is the Tobacco Heating System (THS) 2.2 which does not burn tobacco, but instead heats it, thus producing significantly reduced levels of harmful and potentially harmful constituents (HPHC) compared with combustible cigarettes (CC). A controlled, parallel group, open-label clinical study was conducted with subjects randomized to three monitored groups: (1) switching from CCs to THS2.2; (2) continuous use of non-menthol CC brand (CC arm); or (3) smoking abstinence (SA arm) for five days. Exposure response was assessed by measuring biomarkers of exposure to selected HPHCs. To complement the classical exposure response measurements, we have used the previously reported whole blood derived gene signature that can distinguish current smokers from either non-smokers or former smokers with high specificity and sensitivity. We tested the small signature consisting of only 11 genes on the blood transcriptome of subjects enrolled in the clinical study and showed a reduced exposure response in subjects that either stopped smoking or switched to a candidate MRTP, the THS2.2, compared with subjects who continued smoking their regular tobacco product.
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Project description:Characterizing hookah smoking-induced transcriptional regulations in the human bronchial epithelial cell
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Project description:As part of current harm reduction strategies, candidate modified risk tobacco products (MRTP)s are developed to offer adult smokers who want to continue using tobacco products as an alternative to cigarettes while potentially reducing individual risk and population harm compared to smoking cigarettes. One of these candidate MRTPs is the Tobacco Heating System (THS) 2.2 which does not burn tobacco, but instead heats it, thus producing significantly reduced levels of harmful and potentially harmful constituents (HPHC)s compared with combustible cigarettes (CC). The assessment of MRTPs against combustible cigarettes requires the establishment of exposure-response markers. Biomarkers derived from blood offer for the general population a less invasive alternative than sampling the primary site, such as the airways. Various diseases and exposures, including cigarette smoke, have been shown to alter the molecular profile of the blood. Leveraging this fact, a whole blood derived gene signature that can distinguish current smokers from either non-smokers or former smokers with high specificity and sensitivity was previously reported. Four controlled, parallel randomized groups, open-label clinical studies were conducted with subjects randomized to three groups: (1) switching from CCs to THS2.2 (or its mentholated version, respectively); (2) continuous use of CC; or (3) smoking abstinence. These studies had an investigational period of five days in confinement which was followed by an 85 day ambulatory period for two of them. By measuring biomarkers of exposure to selected HPHCs, these studies showed a consistent reduced exposure in subjects that either stopped smoking or switched to THS2.2 (including mentholated version), compared with subjects who continued smoking their own cigarettes at both day 5 and at day 90. To complement the classical exposure measurements, we tested the small signature consisting of only 11 genes on the blood transcriptome of subjects enrolled in the clinical studies. We show that in all four clinical studies tested, the signature scores were consistently reduced in subjects that either stopped smoking or switched to THS2.2 compared with subjects who continued smoking their conventional tobacco products at both day 6 and at day 91.
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Project description:Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases but switching to less harmful products (modified-risk tobacco products) can be an alternative for smokers who would otherwise not quit. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed the Tobacco Heating System 2.2 (THS 2.2), a candidate modified-risk tobacco product based on the heat-not-burn principle, compared with 3R4F cigarette smoke (CS). To capture toxicity- and disease-relevant mechanisms, we complemented standard toxicology endpoints with in-depth systems toxicology analyses. In this part of our publication series, we report on the integrative assessment of the apical and molecular exposure effects on the respiratory tract (nose, larynx, and lung). Across the respiratory tract, we found differences in the inflammatory response following 3R4F CS exposure (e.g., an antimicrobial peptide response in the nose), and both shared and distinct oxidative and xenobiotic responses. Compared with 3R4F CS, THS 2.2 aerosol exposure exerted far fewer effects on respiratory tract histology, including adaptive tissue changes in nasal and laryngeal epithelium and inflammation and emphysematous changes in the lung. Integrative analysis of the molecular alterations confirmed the substantially lower impact of THS 2.2 aerosol than 3R4F CS on toxicologically and disease-relevant molecular processes such as inflammation, oxidative stress responses, and activation of xenobiotic metabolism. In summary, this work exemplifies how apical and molecular endpoints can be combined effectively for toxicology assessment and further supports reduced respiratory health risks of THS 2.2 aerosol.
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