The time course of expression of genes involved in specific pathways in normal human bronchial epithelial cells following exposure to cigarette smoke.

This study was conducted to determine the time course of gene expression associated with specific signaling pathways in normal human bronchial epithelial (NHBE) cells after exposure to 2 concentrations of 2R4F tobacco mainstream smoke (MSS). Expression of 84 genes representing 18 signal transduction pathways was quantitated in MSS- and air-exposed cultures using real-time polymerase chain reaction (PCR) arrays at 1, 4, and 24 hours following exposure. A confidence score, calculated based on statistical analysis of the degree and reproducibility of expression changes, was used to identify potential biologically significant changes in gene expression. Stimulation of NIAP, an apoptosis inhibitor, suppression of NFKB1 and MYC, representing pro-apoptotic activity, and down-regulation of TCF7 and up-regulation of KLK2, representing anti-/pro-inflammatory responses, were altered 1 hour after exposure to the high concentration of MSS. At the 4-hour time point, the pattern had changed such that 10 different genes were now up-regulated and an additional gene was now down-regulated. Significant changes included genes involved in inflammatory response (LTA, SELPLG, and IL8), repair and wound-healing activity (MMP10), and growth activity (GREB1, EGR1), suggesting repair in this period. By 24 hours, the only up-regulated genes in common with the 4-hour profile were SELPLG and IL8, suggesting continued inflammatory signaling. These results suggest that identification of specific gene expression-based biomarkers of MSS toxicity is promising for investigating specific mechanisms of cellular damage. As expected, the expressed signals were dependent on the concentration of MSS and the postexposure times.