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

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”.

EpiAirway (AIR-100), oxidative stress, xenobiotic metabolism, inflammation, inhibition of nuclear factor-κB, NF-kB, interferon gamma-dependent pathway, proliferation, differentiation, gene set enrichment analysis (GSEA), Vitrocell, reactive oxygen species (ROS), oxidized low-density lipoprotein, nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), KEAP1, Bach1, mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK)1, ERK2, transscription factor AP-1, heat shock genes, endoplasmic reticulum stress, transcription factor (ATF6). X-box binding protein 1, osmotic stress, interferon-g (IFN-g), p53, RB1, E2F4, CDKN1A,E2F1, E2F2, E2F3, CDK4, IL1A, IL1B, IL6, IL13, IL24, IL2CCND1, taof(Myc), heparin binding EGF-like growth factor (HB-EGF), transcription factors AP-155, early growth response protein-1 (EGR-1), phosphatidylinositol 3-kinase (P13K), hepatocyte growth factor (HGF). FGF2, FGF6, FGF7, MUC1, MUC4, MUC13, MUC15, MUC16, MUC20, MUC5AC MUC5B, reverse causal reasoning (RCR), <<...>> miRNA, microRNA

cigarette smoke