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Toxicol Sci. 2016 Feb;149(2):411-32. doi: 10.1093/toxsci/kfv243. Epub 2015 Nov 25.

An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes.

Author information

1
*Philip Morris International Research Laboratories Pte Ltd, The Kendall #02-07, Science Park II, Singapore 117406;
2
Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
3
WK Schlage Biology Consulting, 51429 Bergisch Gladbach, Germany; and.
4
Histovia GmbH, 51491 Overath, Germany.
5
Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland; julia.hoeng@pmi.com.

Abstract

Smoking cigarettes is a major risk factor in the development and progression of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). Modified risk tobacco products (MRTPs) are being developed to reduce smoking-related health risks. The goal of this study was to investigate hallmarks of COPD and CVD over an 8-month period in apolipoprotein E-deficient mice exposed to conventional cigarette smoke (CS) or to the aerosol of a candidate MRTP, tobacco heating system (THS) 2.2. In addition to chronic exposure, cessation or switching to THS2.2 after 2 months of CS exposure was assessed. Engaging a systems toxicology approach, exposure effects were investigated using physiology and histology combined with transcriptomics, lipidomics, and proteomics. CS induced nasal epithelial hyperplasia and metaplasia, lung inflammation, and emphysematous changes (impaired pulmonary function and alveolar damage). Atherogenic effects of CS exposure included altered lipid profiles and aortic plaque formation. Exposure to THS2.2 aerosol (nicotine concentration matched to CS, 29.9 mg/m(3)) neither induced lung inflammation or emphysema nor did it consistently change the lipid profile or enhance the plaque area. Cessation or switching to THS2.2 reversed the inflammatory responses and halted progression of initial emphysematous changes and the aortic plaque area. Biological processes, including senescence, inflammation, and proliferation, were significantly impacted by CS but not by THS2.2 aerosol. Both, cessation and switching to THS2.2 reduced these perturbations to almost sham exposure levels. In conclusion, in this mouse model cessation or switching to THS2.2 retarded the progression of CS-induced atherosclerotic and emphysematous changes, while THS2.2 aerosol alone had minimal adverse effects.

KEYWORDS:

LC-MS based proteomics; atherosclerosis; emphysema; lipidomics; tobacco-heating

PMID:
26609137
PMCID:
PMC4725610
DOI:
10.1093/toxsci/kfv243
[Indexed for MEDLINE]
Free PMC Article

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