title: The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression.
abstract: Gene expression profiling in animal models exposed to cigarette mainstream smoke (CS) shapes up as a promising tool for investigating the molecular mechanisms involved in the onset and development of CS-related disease and may aid in the identification of disease candidate genes. Here we report on differential gene expression in lungs of rats exposed for 2, 7, and 13 weeks to 300 and 600 microg total particulate matter/l CS with sacrifice 2, 6, or 20 h after the last exposure. Regarding antioxidant and xenobiotic-metabolizing (phase I/II) enzymes, a stereotypic, mostly transient, expression pattern of differentially expressed genes was observed after each exposure period. The expression patterns were generally dose dependent for antioxidant and phase II genes and not dose dependent for phase I genes at the CS concentrations tested. However, with increasing length of exposure, there was a distinct, mostly sustained and dose-sensitive, expression of genes implicated in innate and adaptive immune responses, clearly pointing to an emerging inflammatory response. Notably, this inflammatory response included the expression of lung disease-related genes not yet linked to CS exposure, such as galectin-3, arginase 1, and chitinase, as well as genes encoding proteolytic enzymes. Finally, our experiments also revealed a CS exposure-dependent shift in the cyclical expression of genes involved in controlling the circadian rhythm. Altogether, these results provide further insight into the molecular mechanisms of CS-dependent disease onset and development and thus may also be useful for defining CS-specific molecular biomarkers of disease.
authors.affiliation: Philip Morris Research Laboratories GmbH, D-51149 Köln, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gebel
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gerstmayer
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.forename: Kris
authors.initials: K
authors.lastname: Meurrens
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D015870:Gene Expression; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity*; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D012906:Smoke; D015534:Trans-Activators; D015262:Xenobiotics; C538945:Clock protein, rat