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Activated neutrophils inhibit nucleotide excision repair in human pulmonary epithelial cells: role of myeloperoxidase

Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

¹Correspondence: Department of Health Risk Analysis and Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. E-mail: a.knaapen{at}grat.unimaas.nl

Neutrophils are thought to affect pulmonary carcinogenesis by promoting the metabolism of inhaled chemical carcinogens, causing enhanced formation of promutagenic DNA adducts. We hypothesized that neutrophils interfere with the removal of such DNA adducts by inhibiting nucleotide excision repair (NER) in target cells. Human alveolar epithelial cells (A549) were cocultured with activated neutrophils, and we observed a significant reduction of NER in the A549 cells, which was abrogated by addition of the myeloperoxidase (MPO) inhibitor 4-aminobenzoic acid hydrazide. The inhibitory effect of neutrophils could be mimicked by the MPO product hypochlorous acid (HOCl), which caused an acute, dose-dependent inhibition of NER in A549 cells. This was independent of cytotoxicity or ATP loss and persisted up to 24 h. These data were supported by showing that HOCl caused a delayed removal of DNA adducts in benzo[a]pyrene-diolepoxide-exposed A549 cells. The acute HOCl-induced inhibition of NER can only partly be explained by oxidative modification of repair proteins. To explain the more persistent effects of HOCl, we analyzed the expression of NER genes and found that HOCl significantly reduced XPC expression. In conclusion, these data indicate that neutrophils are potent inhibitors of nucleotide excision repair. This may provide a further biological explanation for the association between inflammation and lung cancer development. —Güngör, N., Godschalk, R. W. L., Pachen, D. M., Van Schooten, F. J., Knaapen, A. M. Activated neutrophils inhibit nucleotide excision repair in human pulmonary epithelial cells: role of myeloperoxidase.

Key Words: DNA adducts • DNA repair • inflammation • lung cancer