Modification of the rat airway explant transcriptome by cigarette smoke

Abstract

Although a number of animal model studies have addressed changes in gene expression in the parenchyma and their relationship to emphysema, much less is known about the pathogenesis of cigarette smoke–induced small airway remodeling. In this study the authors exposed rat tracheal explants, a model of the airway wall, to whole smoke for 15 min, and then cultured the explants in air. The airway transcriptome was evaluated using RAE 230_2 gene chips. By 2 h after starting smoke exposure, expression levels of 502 genes were differentially expressed by more than 1.5 times (p < .01 or less) and by 24 h 1870 genes were significantly changed up or down. These included genes involved in antioxidant protection, epithelial defense and remodeling, inflammatory mediators and transcription factors, and a number of unexpected genes, including the matrix metalloproteinase (MMP)-12 inducer, tachykinin-1 (substance P). Pretreatment of the explants with 1 × 10⁻⁷ M dexamethasone reduced the number of significantly changed genes by approximately 47% at 2 h and 68% at 24 h and in almost all instances reduced the magnitude of the smoke-induced changes. The authors conclude that even a very brief exposure to cigarette smoke can lead to rapid changes in the expression of a large number of genes in rat tracheal explants, and that these effects are directly mediated by smoke, without a need for exogenous inflammatory cells. Steroids, contrary to the usual belief, are able to ameliorate many of these changes, at least in this very acute model.

Keywords::

• Airway
• cigarette smoke
• transcriptome

Acknowledgments

We are grateful to Ted Cook, Alistair McLaren, and Richard Stephens for their help with RNA preparation, array hybridizations, and initial analysis of the data, and to Rona Wang for help with the explant preparations. We are also grateful to Darren Gormley for his help managing data files.

Declaration of interest

Supported by GSK and Canadian Institutes of Health Research Industry Partnership Grant 81409 (A.C.). Y.S.L.-B. is a full-time employee of GlaxoSmithKline, J.U.L. and C.L.C. were full-time employees of GlaxoSmithKline.