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.

Project description:Background: Adult vapers are likely to co-use electronic cigarettes (e-cigs) and combustible cigarettes or have a prior history of smoking. Teasing out the health consequences of vaping in adults, while accounting for the confounding effects of smoking, remains a research priority. Methods: We have segregated the biological effects of vaping from smoking by constructing the whole transcriptome in leukocytes of healthy adult vapers (with and without a history of smoking) and exclusive smokers in comparison to control nonsmokers non-vapers (n = 37, 22, 23, respectively). Results: Age- and sex-adjusted limmaVoom analysis of RNA-seq data showed significant dysregulation of key genes and molecular pathways in both vapers and smokers as compared to controls. The extent of transcriptomic effects, as reflected by the number of differentially expressed genes, was more pronounced in smokers than vapers (683 vs. 92). Computational modeling, combining primary and sensitivity analyses, revealed that e-cig use, but not past smoking, is significantly associated with gene dysregulation in vapers. Comparative analysis of the gene networks and canonical pathways impacted in vapers and smokers showed strikingly similar biological outcomes in the two groups, although the number of affected genes was several-fold higher in smokers than vapers. Of significance is the preferential targeting of mitochondrial genes in both vapers and smokers, consistent with impaired functional networks, which are known to drive mitochondrial DNA-related disorders. Equally remarkable is the dysregulation of immune response genes in both vapers and smokers, modulated by upstream cytokines, including members of the interleukin and interferon family, that play a crucial role in inflammation. Conclusions: The concurrent targeting of mitochondrial- and immune response genes in vapers and smokers suggests a consequential role for vaping and smoking in inflammation. Our findings accord with the growing evidence on the central role of mitochondria as signaling organelles that govern fundamentals of immunity and inflammatory response. In view of the widespread use of e-cigs among youth and young adults, these novel findings have significant implications for tobacco regulatory science and public health.

Project description:Chronic obstructive pulmonary disease (COPD) is one of the most prevalent lung diseases, and involves persistent airflow limitation and incorporates both emphysema and chronic bronchitis. Cigarette smoking has been identified as the main risk factor for disease development and progression. In a basic model of COPD, the disease is initiated when the physiologic response mechanisms to cigarette smoke exposure are overwhelmed; for example, because of long-term exposure effects or other aging-related changes. In this parallel-group case-controlled clinical study we asked to what extent the different transitions in a chronic-exposure-to-disease model are reflected in the proteome and cellular transcriptome of induced sputum samples from the lung. For this, we selected 60 age- and gender-matched individuals for each of four study groups: current healthy smokers, current-smoker COPD patients, former smokers, and never smokers (a total of 240 individuals). Induced sputum was collected, the cell-free supernatant was analyzed by quantitative proteomics (isobaric-tag based), and the cellular mRNA fraction was analyzed by microarray-based expression profiling. The sputum proteome of current smokers (healthy or COPD patients) clearly reflected the common physiological responses to smoke exposure, including alterations in mucin/trefoil proteins (e.g., MUC5AC and TFF1/3up-regulation), peptidase regulators (e.g., TIMP1 up-regulation), and a prominent xenobiotic/oxidative stress response (e.g., NQO1 and ALDH3A1 up-regulation). The latter response also was observed in the sputum transcriptome, which additionally demonstrated an immune-related polarization change (toward a M2 signature). The (long-term) former smoker group showed nearly complete reversal of the observable biological effects. Thirteen differentially abundant proteins between the COPD and healthy smoker groups were identified. These abundant proteins included previously reported COPD-associated proteins (e.g., TIMP1 (up-regulation) and APOA1 (down-regulation)) and novel proteins such as C6orf58 and BPIFB1 (LPLUNC1) (both up-regulated in the COPD group compared with the healthy smokers). In summary, our study demonstrates that sputum proteomics/transcriptomics can capture the complex and reversible physiological response to cigarette smoke exposure, which appears to be only slightly modulated in early-stage COPD patients. The study has been registered on ClinicalTrials.gov with identifier NCT01780298.

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Transcriptomic responses in the blood and sputum of cigarette smokers compared to e-cigarette vapers

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