A 6-month inhalation toxicology study in Apoe\u2212/\u2212 mice demonstrates substantially lower effects of e-vapor aerosol compared with cigarette smoke in the respiratory tract

Ee Tsin Wong,Kyeonghee Monica Lee,John H Miller,Tom Lee,Mohamed Amin Choukrallah,Manuel C Peitsch,Patrice Leroy,Rémi Dulize ,Céline Merg ,Arkadiusz K Kuczaj ,Yu‐Tao Xiang ,Emmanuel Guedj,Dariusz Peric,Blaine Phillips,Patrick Vanscheeuwijck,Guo Jie Loh,Karsta Luettich,Oksana Lavrynenko,Bjoern Titz,Sin Kei Wong,Thomas Schneider,Mehdi Auberson,Jovan Simicevic,Nicolas Sierro,Ansgar Buettner,Nikolai V Ivanov,Maica Corciulo,Walter K Schlage,Jingjie Zhang,David Bornand,Justyna Szostak,Julia Hoeng

doi:10.1007/s00204-021-03020-4

Ee Tsin Wong, Kyeonghee Monica Lee + Show 30 more

Open Access

https://doi.org/10.1007/s00204-021-03020-4

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Abstract

Cigarette smoking is the major cause of chronic obstructive pulmonary disease. Considerable attention has been paid to the reduced harm potential of nicotine-containing inhalable products such as electronic cigarettes (e-cigarettes). We investigated the effects of mainstream cigarette smoke (CS) and e-vapor aerosols (containing nicotine and flavor) generated by a capillary aerosol generator on emphysematous changes, lung function, and molecular alterations in the respiratory system of female Apoe−/− mice. Mice were exposed daily (3 h/day, 5 days/week) for 6 months to aerosols from three different e-vapor formulations—(1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine), or (3) test (base and flavor)—or to CS from 3R4F reference cigarettes. The CS and base/test aerosol concentrations were matched at 35 µg nicotine/L. CS exposure, but not e-vapor exposure, led to impairment of lung function (pressure–volume loop area, A and K parameters, quasi-static elastance and compliance) and caused marked lung inflammation and emphysematous changes, which were confirmed histopathologically and morphometrically. CS exposure caused lung transcriptome (activation of oxidative stress and inflammatory responses), lipidome, and proteome dysregulation and changes in DNA methylation; in contrast, these effects were substantially reduced in response to the e-vapor aerosol exposure. Compared with sham, aerosol exposure (carrier, base, and test) caused a slight impact on lung inflammation and epithelia irritation. Our results demonstrated that, in comparison with CS, e-vapor aerosols induced substantially lower biological and pathological changes in the respiratory tract associated with chronic inflammation and emphysema.

Highlights

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is among the leading causes of morbidity and mortality (Lopez-Campos et al 2016; Quaderi and Hurst 2018)
COPD is defined as a “preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases” (GOLD-COPD 2019)
The objective of this study was to assess the impact of exposure to unflavored and flavored e-vapor aerosols generated using a capillary aerosol generator on the respiratory system and to comparatively evaluate COPD-related changes, as well as the underlying molecular changes relative to those observed after exposure to Cigarette smoke (CS) in Apoe−/− mice

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is among the leading causes of morbidity and mortality (Lopez-Campos et al 2016; Quaderi and Hurst 2018). Cigarette smoking is the predominant cause of COPD in industrialized countries and accounts for more than 95% of cases (Barnes et al 2003; Buist et al 2008; Churg et al 2008). Cigarette smoke (CS) exposure exacerbates and perpetuates inflammation, causing airway remodeling, airway obstruction, and emphysematous changes characteristic of COPD

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