Project description:Cigarette smoking exerts diverse physiological effects including immune suppression. Existing US epidemiological data show that consumption of smokeless tobacco products, such as moist snuff, is less harmful relative to cigarette smoking. In efforts to understand the molecular changes due to consumption of different tobacco product classes, we have shown recently that smokers exhibit distinct peripheral blood mononuclear cells (PBMCs) gene expression patterns relative to moist snuff users and non-tobacco consumers (NTCs). To better characterize the biological effects exerted from the use of different tobacco products, a genome-wide gene expression study, using a cultured PBMC model, was performed. Gene expression profiles from PBMCs treated with low equi-nicotine units (0.3 µg/ml) of WS-CM and a single high dose of STE (100 µg/ml) were similar to those from untreated controls. Cells treated with medium and high equi-nicotine unit doses of WS-CM (1.0 and 3.0 µg/ml) exhibited significantly different gene expression profiles compared to the low equi-nicotine WS-CM dose and STE. Pre-treatment with higher doses of WS-CM inhibited the expression of several pro-inflammatory genes that regulate immune responses, including IFNγ, TNFα, and IL-2. Gene expression changes of these genes and other cytokine signaling genes were confirmed by qRT-PCR. Moreover, secretion of IFNγ, TNFα and IL-2 proteins was abolished by WS-CM pre-treatment even after 24 hours of toll like receptor stimulation. Additionally, pathway analyses revealed that higher doses of WS-CM inhibited NF-ĸβ signaling and a wide range of signaling pathways associated with immune cell differentiation and inflammatory responses, and increased expression of genes involved in apoptosis. Collectively, our results show that pre-treatment of PBMCs with higher doses of WS-CM inhibits immune activation and effector cytokine expression and secretion, resulting in a reduced immune response, whereas STE had minimal effect.

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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Distinct gene expression changes in human peripheral blood mononuclear cells treated with different tobacco product preparations

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