title: Lung inflammation is associated with reduced pulmonary nucleotide excision repair in vivo.
abstract: 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 microg), 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 approximately 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.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Nejla
authors.initials: N
authors.lastname: Güngör
authors.forename: Astrid
authors.initials: A
authors.lastname: Haegens
authors.forename: Ad M
authors.initials: AM
authors.lastname: Knaapen
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Roland K
authors.initials: RK
authors.lastname: Chiu
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D051760:Xeroderma Pigmentosum Group A Protein; C095888:xeroderma pigmentosum group F protein; D009195:Peroxidase