title: Impact Assessment of Cigarette Smoke Exposure on Organotypic Bronchial Epithelial Tissue Cultures: A Comparison of Mono-Culture and Coculture Model Containing Fibroblasts.
abstract: Organotypic 3D cultures of epithelial cells are grown at the air-liquid interface (ALI) and resemble the in vivo counterparts. Although the complexity of in vivo cellular responses could be better manifested in coculture models in which additional cell types such as fibroblasts were incorporated, the presence of another cell type could mask the response of the other. This study reports the impact of whole cigarette smoke (CS) exposure on organotypic mono- and coculture models to evaluate the relevancy of organotypic models for toxicological assessment of aerosols. Two organotypic bronchial models were directly exposed to low and high concentrations of CS of the reference research cigarette 3R4F: monoculture of bronchial epithelial cells without fibroblasts (BR) and coculture with fibroblasts (BRF) models. Adenylate kinase (AK)-based cytotoxicity, cytochrome P450 (CYP) 1A1/1B1 activity, tissue histology, and concentrations of secreted mediators into the basolateral media, as well as transcriptomes were evaluated following the CS exposure. The results demonstrated similar impact of CS on the AK-based cytotoxicity, CYP1A1/1B1 activity, and tissue histology in both models. However, a greater number of secreted mediators was identified in the basolateral media of the monoculture than in the coculture models. Furthermore, annotation analysis and network-based systems biology analysis of the transcriptomic profiles indicated a more prominent cellular stress and tissue damage following CS in the monoculture epithelium model without fibroblasts. Finally, our results indicated that an in vivo smoking-induced xenobiotic metabolism response of bronchial epithelial cells was better reflected from the in vitro CS-exposed coculture model.
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland Anita.iskandar@pmi.com.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Iskandar
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuehn
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: Philip Morris International R&D, 2000 Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D001980:Bronchi / Q000473:pathology*; D018920:Coculture Techniques; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020545:Respiratory Mucosa / Q000473:pathology*; D012906:Smoke / Q000009:adverse effects*; D046509:Tissue Culture Techniques; D062789:Tobacco Products
chemical_list: D012906:Smoke; D003577:Cytochrome P-450 Enzyme System; D000263:Adenylate Kinase
keywords: aerosol; air–liquid interface; biological network; coculture; transcriptomic