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ToxSci Advance Access published online on July 26, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl071
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received May 23, 2006
Accepted July 23, 2006

Respiratory Toxicology

The Kinetics of Transcriptomic Changes Induced by Cigarette Smoke in Rat Lungs Reveals a Specific Program of Defense, Inflammation, and Circadian Clock Gene Expression

Stephan Gebel 1, Bernhard Gerstmayer 2, Peter Kuhl 1, Jürgen Borlak 3, Kris Meurrens 4, and Thomas Müller 1 *

1 PHILIP MORRIS Research Laboratories GmbH, Fuggerstr. 3, D-51149 Köln, Germany
2 Miltenyi Biotec GmbH, Stöckheimer Weg 1, D-50829 Köln, Germany
3 Fraunhofer-Institut für Toxikologie und Experimentelle Medizin, Nikolai-Fuchs-Straße 1, D-30625 Hannover, Germany
4 PHILIP MORRIS Research Laboratories bvba, Grauwmeer 14, B-3001 Leuven, Belgium

* To whom correspondence should be addressed.
Thomas Müller, E-mail: thomas.mueller{at}pmintl.com


  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 µg total particulate matter (TPM)/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.

Keywords: cigarette smoke; circadian rhythm; inflammation; oxidative stress; rat lung; gene expression.
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