The transcriptome of Nrf2-/- mice provides evidence for impaired cell cycle progression in the development of cigarette smoke-induced emphysematous changes.
Cigarette smoke (CS) imposes a strong oxidative burden on exposed tissues resulting in a severely disturbed oxidant/antioxidant balance, which in the context of chronic exposure is assumed to be a key contributor to CS-related diseases. Because of its emerging central role in orchestrating the general cellular antioxidant response, the pathway leading to the activation of the transcription factor Nrf2 has received mounting attention over the past decade in investigations aimed at elucidating CS-induced pathophysiological mechanisms. To comprehensively characterize the impact of Nrf2 in acute and subchronic smoking scenarios, Nrf2(-/-) mice and their wild-type (wt) ICR littermates were exposed to either ambient air (sham exposure) or one of three doses of CS for up to 5 months, with two postexposure endpoints of 1 and 13 days. The lungs of the mice were monitored for transcriptomic changes on a genome-wide level, which confirmed an impaired expression of antioxidant and phase 2-related genes in CS-exposed Nrf2(-/-) mice. Importantly, in comparison to wt mice, an attenuated cell cycle/mitotic response and intensified stress gene expression pattern were observed in exposed Nrf2(-/-) mice, which was paralleled by clear dose-dependent effects on alveolar destruction and impaired lung function. In contrast, the inflammation-related transcriptional response and scores for various bronchioalveolar inflammation parameters were qualitatively and quantitatively similar in CS-exposed mice of both genotypes. Taken together, these results confirm the protective nature of Nrf2 in oxidative stress scenarios and suggest that the enhanced emphysematous phenotype exhibited by CS-exposed Nrf2(-/-) mice is more likely caused by an imbalance in cell loss and regeneration than by increased inflammation.
Philip Morris Research Laboratories GmbH, Philip Morris International Research & Development, Köln, Germany.
Stephan
S
Gebel
Svenja
S
Diehl
Jan
J
Pype
Bärbel
B
Friedrichs
Horst
H
Weiler
Jutta
J
Schüller
Haiyan
H
Xu
Keiko
K
Taguchi
Masayuki
M
Yamamoto
Thomas
T
Müller
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001947:Breeding; D002453:Cell Cycle / Q000235:genetics*; D004195:Disease Models, Animal; D004646:Emphysema / Q000139:chemically induced / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012906:Smoke