title: A systems biology approach reveals the dose- and time-dependent effect of primary human airway epithelium tissue culture after exposure to cigarette smoke in vitro.
abstract: To establish a relevant in vitro model for systems toxicology-based mechanistic assessment of environmental stressors such as cigarette smoke (CS), we exposed human organotypic bronchial epithelial tissue cultures at the air liquid interface (ALI) to various CS doses. Previously, we compared in vitro gene expression changes with published human airway epithelia in vivo data to assess their similarities. Here, we present a follow-up evaluation of these in vitro transcriptomics data, using complementary computational approaches and an integrated mRNA-microRNA (miRNA) analysis. The main cellular pathways perturbed by CS exposure were related to stress responses (oxidative stress and xenobiotic metabolism), inflammation (inhibition of nuclear factor-κB and the interferon gamma-dependent pathway), and proliferation/differentiation. Within post-exposure periods up to 48 hours, a transient kinetic response was observed at lower CS doses, whereas higher doses resulted in more sustained responses. In conclusion, this systems toxicology approach has potential for product testing according to "21st Century Toxicology".
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Carole
authors: C
authors: Mathis
authors: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Cologne, Germany.
authors: Stephan
authors: S
authors: Gebel
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Carine
authors: C
authors: Poussin
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Vincenzo
authors: V
authors: Belcastro
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Alain
authors: A
authors: Sewer
authors: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Cologne, Germany.
authors: Dirk
authors: D
authors: Weisensee
authors: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Cologne, Germany.
authors: Arnd
authors: A
authors: Hengstermann
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Sam
authors: S
authors: Ansari
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Sandra
authors: S
authors: Wagner
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Manuel C
authors: MC
authors: Peitsch
authors: Philip Morris International R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
authors: Julia
authors: J
authors: Hoeng
keywords: air liquid interface; cigarette smoke; mechanistic investigations; organotypic culture; systems biology