title: 3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product.
abstract: In vitro toxicology approaches have evolved from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offers a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus, the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. Aligned with 3Rs strategy, this study aimed to explore the relevance of a human 3-D nasal culture model to assess the toxicological impact of aerosols generated from a candidate modified risk tobacco product (cMRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F. A series of experimental repetitions, where multiple concentrations of THS2.2 aerosol and 3R4F smoke were applied, were conducted to obtain reproducible measurements to understand the cellular/molecular changes that occur following exposure. In agreement with "Toxicity Testing in the 21st Century - a Vision and a Strategy", this study implemented a systems toxicology approach and found that for all tested concentrations the impact of 3R4F smoke was substantially greater than that of THS2.2 aerosol in terms of cytotoxicity levels, alterations in tissue morphology, secretion of pro-inflammatory mediators, impaired ciliary function, and increased perturbed transcriptomes and miRNA expression profiles.
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Iskandar
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Sewer
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Shoaib
authors.initials: S
authors.lastname: Majeed
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuehn
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Keyur
authors.initials: K
authors.lastname: Trivedi
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Grandolfo
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Cabanski
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Merg
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000336:Aerosols; D023401:Animal Use Alternatives; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D019570:Inhalation Exposure; D008954:Models, Biological; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects / Q000032:analysis*; D062789:Tobacco Products
chemical_list: D000336:Aerosols; D012906:Smoke
keywords: air-liquid interface; cigarette smoke; modified risk tobacco product; organotypic culture; systems toxicology