Evaluation of the Tobacco Heating System 2.2 (THS2.2). Part 5: microRNA expression from a 90-day rat inhalation study indicates that exposure to THS2.2 aerosol causes reduced effects on lung tissue compared with cigarette smoke

Abstract We conducted an inhalation study, in accordance with Organisation for Economic Co-operation and Development Test Guideline 453, exposing A/J mice to tobacco heating system (THS) 2.2 aerosol or 3R4F reference cigarette smoke (CS) for up to 18 months to evaluate chronic toxicity and carcinogenicity. All exposed mice showed lower thymus and spleen weight, blood lymphocyte counts, and serum lipid concentrations than sham mice, most likely because of stress and/or nicotine effects. Unlike THS 2.2 aerosol-exposed mice, CS-exposed mice showed increased heart weight, changes in red blood cell profiles and serum liver function parameters. Similarly, increased pulmonary inflammation, altered lung function, and emphysematous changes were observed only in CS-exposed mice. Histopathological changes in other respiratory tract organs were significantly lower in the THS 2.2 aerosol-exposed groups than in the CS-exposed group. Chronic exposure to THS 2.2 aerosol also did not increase the incidence or multiplicity of bronchioloalveolar adenomas or carcinomas relative to sham, whereas CS exposure did. Male THS 2.2 aerosol-exposed mice had a lower survival rate than sham mice, related to an increased incidence of urogenital issues that appears to be related to congenital factors rather than test item exposure. The lower impact of THS 2.2 aerosol exposure on tumor development and chronic toxicity is consistent with the significantly reduced levels of harmful and potentially harmful constituents in THS 2.2 aerosol relative to CS. The totality of the evidence from this study further supports the risk reduction potential of THS 2.2 for lung diseases in comparison with cigarettes.

Download Full-text

A 7-month inhalation toxicology study in C57BL/6 mice demonstrates reduced pulmonary inflammation and emphysematous changes following smoking cessation or switching to e-vapor products

Toxicology Research and Application ◽

10.1177/2397847321995875 ◽

2021 ◽

Vol 5 ◽

pp. 239784732199587

Author(s):

Ashutosh Kumar ◽

Ulrike Kogel ◽

Marja Talikka ◽

Celine Merg ◽

Emmanuel Guedj ◽

...

Keyword(s):

Smoking Cessation ◽

Cigarette Smoke ◽

Pulmonary Inflammation ◽

Clinical Signs ◽

Inhalation Study ◽

Toxicology Study ◽

Nasal Tissue ◽

Product Switching ◽

The Impact

Cigarette smoking causes serious diseases, including lung cancer, atherosclerotic coronary artery disease, peripheral vascular disease, chronic bronchitis, and emphysema. While cessation remains the most effective approach to minimize smoking-related disease, alternative non-combustible tobacco-derived nicotine-containing products may reduce disease risks among those unable or unwilling to quit. E-vapor aerosols typically contain significantly lower levels of smoke-related harmful and potentially harmful constituents; however, health risks of long-term inhalation exposures are unknown. We designed a 7-month inhalation study in C57BL/6 mice to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation (Cessation group) or switching to an e-vapor product (Switching group) after 3 months of exposure to 3R4F cigarette smoke (CS). There were no significant changes in in-life observations (body weights, clinical signs) in e-vapor groups compared to the Sham Control. The 3R4F CS group showed reduced respiratory function during exposure and had lower body weight and showed transient signs of distress post-exposure. Following 7 months of exposure, e-vapor aerosols resulted in no or minimal increase in pulmonary inflammation, while exposure to 3R4F CS led to impairment of lung function and caused marked lung inflammation and emphysematous changes. Biological changes observed in the Switching group were similar to the Cessation group. 3R4F CS exposure dysregulated the lung and nasal tissue transcriptome, while these molecular effects were substantially lower in the e-vapor group. Results from this study demonstrate that in comparison with 3R4F CS, e-vapor aerosols induce substantially lower biological responses including pulmonary inflammation and emphysematous changes, and that complete switching from CS to e-vapor products significantly reduces biological changes associated with CS in C57BL/6 mice.

Download Full-text

Transcriptomic Analysis of Lung Tissue from Cigarette Smoke–Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2016-0328oc ◽

2017 ◽

Vol 57 (1) ◽

pp. 47-58 ◽

Cited By ~ 22

Author(s):

Jeong H. Yun ◽

Jarrett Morrow ◽

Caroline A. Owen ◽

Weiliang Qiu ◽

Kimberly Glass ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Lung Tissue ◽

Transcriptomic Analysis ◽

Chronic Obstructive ◽

Murine Models ◽

Obstructive Pulmonary Disease

Download Full-text

Robustness of HPHC Reduction in THS 2.2 Aerosol Relative to 3R4F Reference Cigarette Smoke under Extreme Climatic Conditions

Contributions to Tobacco & Nicotine Research ◽

10.2478/cttr-2021-0008 ◽

2021 ◽

Vol 30 (3) ◽

pp. 109-126

Author(s):

Laurent Poget ◽

Catherine Goujon ◽

Samuel Kleinhans ◽

Serge Maeder ◽

Jean-Pierre Schaller

Keyword(s):

Cigarette Smoke ◽

Heating System ◽

Tobacco Product ◽

Climatic Conditions ◽

Mainstream Smoke ◽

Humid Climate ◽

Experimental Conditions ◽

Puff Volume ◽

Temperature And Humidity ◽

Health Canada

Summary In order to assess robustness for the reduction of harmful and potentially harmful constituent (HPHC) levels generated by the Tobacco Heating System 2.2 (THS 2.2), a heated tobacco product, we compared the aerosol of this product with mainstream smoke from the 3R4F reference cigarette under different conditions of temperature and humidity. The desired climatic conditions were achieved by using an air-conditioning system coupled with the smoking-machine housing. Two extreme climatic conditions were selected, representing a “Hot and Dry” climate (30 °C and 35% relative humidity RH) and a “Hot and Very Humid” climate (30 °C and 75% RH). In addition, aerosol and smoke were generated using the standard conditions recognized for smoking-machine analyses of tobacco products (22 °C and 60% RH), which were close to the climatic conditions defined for “Subtropical and Mediterranean” environments (25 °C and 60% RH). The experimental conditions were chosen to simulate the use of THS 2.2 and cigarettes under extreme conditions of temperature and humidity. HeatSticks and cigarettes taken from freshly opened packs were subjected to short-term conditioning from two to a few more days under the same experimental conditions. We analyzed 54 HPHCs in THS 2.2 aerosol and 3R4F cigarette smoke, generated in accordance with the Health Canada Intense (HCI) standard, using modified temperature and humidity conditions for sample conditioning and machine-smoking experiments. We used a volume-adjusted approach for comparing HPHC reductions across the different climatic conditions investigated. Although a single puffing regimen was used, the total puff volume recorded for the 3R4F cigarette smoke varied due to the influence of temperature and humidity on combustion rate, which justified the use of a volume-adjusted approach. Volume-adjusted yields were derived from HPHC yields expressed in mass-per-tobacco stick normalized per total puff volume. The results indicated that, regardless of the considered climatic conditions, the HPHC levels investigated in THS 2.2 aerosol were reduced by at least 90%, on average, when compared with the concentrations in 3R4F cigarette mainstream smoke. This confirmed the robustness in performance for THS 2.2 to deliver reduced levels of HPHCs under the extreme climatic conditions investigated in this study. In order to further characterize the robustness of these reductions, the lowest reduction performance achieved for individual HPHCs across all climatic conditions was used to define the threshold for a robust reduction. The majority of the 54 HPHCs investigated in THS 2.2 aerosol showed more than 90% reduction. Calculations derived from nicotine-adjusted yields also confirmed robust reductions for all investigated HPHCs. The small differences in absolute reduction between the volume- and nicotine-adjusted approaches were predominantly attributed to a combination of the differences in both nominal nicotine deliveries and total puff volumes between THS 2.2 and 3R4F cigarettes; however, this did not influence the determination of robustness. Our findings confirm the value of this approach for assessing the robustness of a product’s performance under different climatic conditions.

Download Full-text

Cigarette smoke inhalation study for lung tumorigenicity in A/J mice

Journal of Bioequivalence & Bioavailability ◽

10.4172/0975-0851.1000063 ◽

2010 ◽

Vol 01 (01) ◽

Author(s):

R. B. Lichtner ◽

B. Friedrichs ◽

A. Buettner ◽

F. Van Overveld ◽

W. Stinn

Keyword(s):

Cigarette Smoke ◽

Smoke Inhalation ◽

Inhalation Study

Download Full-text

Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients

Scientific Reports ◽

10.1038/s41598-019-49648-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Giulia Pintarelli ◽

Sara Noci ◽

Davide Maspero ◽

Angela Pettinicchio ◽

Matteo Dugo ◽

...

Keyword(s):

Gene Expression ◽

Lung Adenocarcinoma ◽

Cigarette Smoke ◽

Lung Tissue ◽

Gene Networks ◽

Lung Parenchyma ◽

Fold Change ◽

Differentially Expressed ◽

Significant Gene ◽

Never Smokers

Abstract Alterations in the gene expression of organs in contact with the environment may signal exposure to toxins. To identify genes in lung tissue whose expression levels are altered by cigarette smoking, we compared the transcriptomes of lung tissue between 118 ever smokers and 58 never smokers. In all cases, the tissue studied was non-involved lung tissue obtained at lobectomy from patients with lung adenocarcinoma. Of the 17,097 genes analyzed, 357 were differentially expressed between ever smokers and never smokers (FDR < 0.05), including 290 genes that were up-regulated and 67 down-regulated in ever smokers. For 85 genes, the absolute value of the fold change was ≥2. The gene with the smallest FDR was MYO1A (FDR = 6.9 × 10−4) while the gene with the largest difference between groups was FGG (fold change = 31.60). Overall, 100 of the genes identified in this study (38.6%) had previously been found to associate with smoking in at least one of four previously reported datasets of non-involved lung tissue. Seven genes (KMO, CD1A, SPINK5, TREM2, CYBB, DNASE2B, FGG) were differentially expressed between ever and never smokers in all five datasets, with concordant higher expression in ever smokers. Smoking-induced up-regulation of six of these genes was also observed in a transcription dataset from lung tissue of non-cancer patients. Among the three most significant gene networks, two are involved in immunity and inflammation and one in cell death. Overall, this study shows that the lung parenchyma transcriptome of smokers has altered gene expression and that these alterations are reproducible in different series of smokers across countries. Moreover, this study identified a seven-gene panel that reflects lung tissue exposure to cigarette smoke.

Download Full-text

AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract

Chinese Science Bulletin ◽

10.1007/s11434-011-4437-8 ◽

2011 ◽

Vol 56 (15) ◽

pp. 1562-1568 ◽

Cited By ~ 2

Author(s):

JunLi Li ◽

Yan Chen ◽

Ping Chen ◽

Shan Cai ◽

Hong Peng ◽

...

Keyword(s):

Cigarette Smoke ◽

Lung Tissue ◽

Cell Apoptosis ◽

Cigarette Smoke Extract

Download Full-text

Humic-like substances in cigarette smoke condensate and lung tissue of smokers

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.4.l382 ◽

1994 ◽

Vol 266 (4) ◽

pp. L382-L388 ◽

Cited By ~ 6

Author(s):

A. J. Ghio ◽

J. Stonehuerner ◽

D. R. Quigley

Keyword(s):

Free Radical ◽

Cigarette Smoke ◽

Lung Tissue ◽

Cigarette Smoke Exposure ◽

Cigarette Smoke Condensate ◽

Free Radical Generation ◽

Carboxylate Content ◽

Radical Generation

Deposition of pigmented matter in the lower respiratory tract correlates with the extent of emphysema in smokers as well as with free radical generation and iron accumulation. Pulmonary emphysema is postulated to be mediated by free radical generation which is either directly or indirectly associated with cigarette smoke exposure. The hypothesis was tested that 1) incomplete combustion of tobacco yields humic-like substances (HLS) which 2) deposit in the lung as pigmented particulates, 3) complex iron cations in vitro and in vivo, and 4) have a capacity to catalyze oxidant formation. HLS, isolated by alkali extraction of cigarette smoke condensate (CSC) (Tobacco Health Research Institute, University of Kentucky), demonstrated a high carbon and low carboxylate content on elemental and functional group analyses, respectively, compared with values for HLS sequestered from soils. The HLS isolated from CSC had a capacity to complex iron in vitro and accumulated the metal in vivo after intratracheal instillation in an animal model. Both HLS and its iron complex generated free radicals, and some portion of this oxidant generation was metal dependent. Lung tissue collected at autopsy from smokers contained HLS with an infrared spectrum almost identical to that of the material isolated from CSC. Associations between particulate deposition, metal accumulation, and free radical generation suggest a possible role of HLS in the induction of lung disease following cigarette exposure.

Download Full-text