Journal Article

Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke

Stephan Gebel, Bernhard Gerstmayer, Andreas Bosio, Hans-Jürgen Haussmann, Erik Van Miert and Thomas Müller

in Carcinogenesis

Volume 25, issue 2, pages 169-178
Published in print February 2004 | ISSN: 0143-3334
Published online February 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg193
Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke

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Cigarette smoke (CS) is known to cause cancer and other diseases, but little is known about the global molecular and cellular changes that occur prior to the appearance of clinically detectable symptoms. Using DNA microarrays covering 2031 cDNA probes, we investigated differential gene expression in tissues of the rat respiratory tract, i.e. respiratory nasal epithelium (RNE) and lungs of rats exposed either acutely (3 h) or subchronically (3 h/day, 5 days/week, 3 weeks) to mainstream CS with death either immediately or at 20 h after exposure. Differential gene expression was most evident in RNE of rats exposed once and was characterized by strong up-regulation of genes encoding oxidative stress-responsive and Phase II drug-metabolizing enzymes, such as haem oxygenase-1 and NAD(P)H:quinone oxidoreductase, which are all, at least in part, transcriptionally regulated by NF-E2-related factor 2 (Nrf2). After 3 weeks of exposure, the strength of expression of this class of genes was markedly reduced, pointing to an adaptive response. The generally lower response in the lungs of exposed rats is indicative of a deposition gradient of active smoke constituents from the upper to the lower respiratory tract. In sharp contrast to the CS-induced expression of oxidative stress and Phase II-responsive genes, induction of the genes encoding the Phase I drug-metabolizing enzymes cytochrome P450 (CYP)1A1 and aldehyde dehydrogenase-3 was not reduced after 3 weeks of exposure and was similarly high in lungs and RNE. Gene expression patterns in rats allowed to recover for 20 h showed that the CS-induced transcriptional changes observed immediately after exposure returned almost completely to normal, even after 3 weeks of repeated CS exposure. In general, these results demonstrate that CS induces a specific differential gene expression pattern in vivo, which may be instrumental in identifying the molecular mechanisms leading to the onset of inflammatory and/or morphological changes.

Keywords: Ah, aryl hydrocarbon; ALDH3, cytosolic class-3 aldehyde dehydrogenase; ARE, antioxidant response element; aRNA, amplified RNA; B[a]P, benzo[a]pyrene; CS, cigarette smoke; CYP, cytochrome P450; DBP, D-site-binding protein; FIZZ, found in inflammatory zone; GSH, glutathione; HO-1, haem oxygenase-1; HSP, heat shock protein; IL, Interleukin; MT, metallothionein; NQO-1, NAD(P)H:quinone oxireductase; Nrf2, NF-E2-related factor 2; PAHs, polycyclic aromatic hydrocarbons; RELM, resistin-like molecule; RNE, respiratory nasal epithelium; SATT, neutral amino acid transporter A; TPM, total particulate matter; UGT, UDP-glucuronosyltransferase; γGCS, γ-glutamyl-cysteine-synthetase; γGT1, γ-glutamyl-transpeptidase.

Journal Article.  8646 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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