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Mutagenesis Advance Access published online on November 16, 2009
Mutagenesis, doi:10.1093/mutage/gep049
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© The Author 2009. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Lung inflammation is associated with reduced pulmonary nucleotide excision repair in vivo

Nejla Güngör1,3, Astrid Haegens2, Ad M. Knaapen1,4, Roger W.L. Godschalk1, Roland K. Chiu1, Emiel F.M. Wouters2 and Frederik J. van Schooten1,*

1Department of Health Risk Analysis and Toxicology 2Department of Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands

Chronic pulmonary inflammation is associated with increased lung cancer risk, but the underlying process remains unknown. Recently, we showed that activated neutrophils inhibit nucleotide excision repair (NER) in pulmonary epithelial cells in vitro via the release of myeloperoxidase (MPO). To evaluate the effect of neutrophils on NER in vivo, mice were intratracheally instilled with lipopolysaccharide (LPS) (20 µg), causing acute lung inflammation and associated neutrophil influx into the airways. Three days post-exposure, phenotypical NER capacity was assessed in lung tissue homogenate. LPS exposure inhibited pulmonary NER by ~50%. This finding was corroborated by down-regulation of the NER-associated genes Xpa and Xpf. To further elicit the role of neutrophils and MPO in this process, we utilized MPO-deficient mice as well as mice in which circulating neutrophils were depleted by antibody treatment. LPS-induced inhibition of pulmonary NER was not affected by either Mpo–/– or by depletion of circulating neutrophils. This contrasts with our previous in vitro observations, suggesting that inhibition of pulmonary NER following acute dosing with LPS is not fully mediated by neutrophils and/or MPO. In conclusion, these data show that LPS-induced pulmonary inflammation is associated with a reduction of NER function in the mouse lung.

* To whom correspondence should be addressed. Tel: +31 43 3881100; Fax: +31 43 3884146; Email: f.vanschooten{at}grat.unimaas.nl

3 Present address: MAASTRO/GROW, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands

4 Present address: Department of Toxicology and Drug Disposition, Schering-Plough, PO Box 20, 5340 BH Oss, The Netherlands

Received on July 14, 2009; revised on October 7, 2009; accepted on October 7, 2009.


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