title: Effects of Cigarette Smoke, Cessation, and Switching to Two Heat-Not-Burn Tobacco Products on Lung Lipid Metabolism in C57BL/6 and Apoe-/- Mice-An Integrative Systems Toxicology Analysis.
abstract: The impact of cigarette smoke (CS), a major cause of lung diseases, on the composition and metabolism of lung lipids is incompletely understood. Here, we integrated quantitative lipidomics and proteomics to investigate exposure effects on lung lipid metabolism in a C57BL/6 and an Apolipoprotein E-deficient (Apoe(-/-)) mouse study. In these studies, mice were exposed to high concentrations of 3R4F reference CS, aerosol from potential modified risk tobacco products (MRTPs) or filtered air (Sham) for up to 8 months. The 2 assessed MRTPs, the prototypical MRTP for C57BL/6 mice and the Tobacco Heating System 2.2 for Apoe(-/-) mice, utilize "heat-not-burn" technologies and were each matched in nicotine concentrations to the 3R4F CS. After 2 months of CS exposure, some groups were either switched to the MRTP or underwent cessation. In both mouse strains, CS strongly affected several categories of lung lipids and lipid-related proteins. Candidate surfactant lipids, surfactant proteins, and surfactant metabolizing proteins were increased. Inflammatory eicosanoids, their metabolic enzymes, and several ceramide classes were elevated. Overall, CS induced a coordinated lipid response controlled by transcription regulators such as SREBP proteins and supported by other metabolic adaptations. In contrast, most of these changes were absent in the mice exposed to the potential MRTPs, in the cessation group, and the switching group. Our findings demonstrate the complex biological response of the lungs to CS exposure and support the benefits of cessation or switching to a heat-not-burn product using a design such as those employed in this study.
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland; *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland; julia.hoeng@pmi.com.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Titz
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boué
authors.affiliation: Philip Morris International Research Laboratories, 50 Science Park Road, Singapore, Singapore; and.
authors.forename: Blaine
authors.initials: B
authors.lastname: Phillips
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.affiliation: Zora Biosciences Oy, Biologinkuja 1, 02150 Espoo, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Vihervaara
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Catherine
authors.initials: C
authors.lastname: Nury
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Ashraf
authors.initials: A
authors.lastname: Elamin
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Peck
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Maciej
authors.initials: M
authors.lastname: Cabanski
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Gregory
authors.initials: G
authors.lastname: Vuillaume
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Emilija
authors.initials: E
authors.lastname: Veljkovic
authors.affiliation: Zora Biosciences Oy, Biologinkuja 1, 02150 Espoo, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Ekroos
authors.affiliation: Zora Biosciences Oy, Biologinkuja 1, 02150 Espoo, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanscheeuwijck
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland;
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: *Philip Morris International Research and Development, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland; julia.hoeng@pmi.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D050356:Lipid Metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D020543:Proteome; D012906:Smoke / Q000009:adverse effects*; D013107:Sphingolipids / Q000378:metabolism; D062789:Tobacco Products
chemical_list: D001057:Apolipoproteins E; D015777:Eicosanoids; D020543:Proteome; D012906:Smoke; D013107:Sphingolipids
keywords: lipidomics; modified risk tobacco products; quantitative proteomics; systems toxicology