title: 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.
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.
authors.affiliation: *Philip Morris International Research Laboratories Pte Ltd, The Kendall #02-07, Science Park II, Singapore 117406;
authors.forename: Blaine
authors.initials: B
authors.lastname: Phillips
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Emilija
authors.initials: E
authors.lastname: Veljkovic
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boué
authors.affiliation: WK Schlage Biology Consulting, 51429 Bergisch Gladbach, Germany; and.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Gregory
authors.initials: G
authors.lastname: Vuillaume
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Bjoern
authors.initials: B
authors.lastname: Titz
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: Histovia GmbH, 51491 Overath, Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Buettner
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Ashraf
authors.initials: A
authors.lastname: Elamin
authors.affiliation: *Philip Morris International Research Laboratories Pte Ltd, The Kendall #02-07, Science Park II, Singapore 117406;
authors.forename: Alberto
authors.initials: A
authors.lastname: Oviedo
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Maciej
authors.initials: M
authors.lastname: Cabanski
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Héctor
authors.initials: H
authors.lastname: De León
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanscheeuwijck
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland;
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., 2000 Neuchâtel, Switzerland; julia.hoeng@pmi.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology; D002318:Cardiovascular Diseases / Q000209:etiology*; D004646:Emphysema / Q000209:etiology; D005260:Female; D019570:Inhalation Exposure; D008168:Lung / Q000473:pathology; D008170:Lung Compliance; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
chemical_list: D001057:Apolipoproteins E; D012906:Smoke
keywords: LC-MS based proteomics; atherosclerosis; emphysema; lipidomics; tobacco-heating