Lung inflammation is associated with reduced pulmonary nucleotide excision repair in vivo
Lung inflammation is associated with reduced pulmonary nucleotide excision repair in vivo
复制标题
DOI：
10.1093/mutage/gep049
复制
发表时间：
2010-01-01
期刊：
影响因子：
2.7
通讯作者：
van Schooten, Frederik J.
中科院分区：
文献类型：
--
作者：
Gungor, Nejla;Haegens, Astrid;van Schooten, Frederik J.
慢性肺部炎症与肺癌风险增加有关，但其潜在过程仍不清楚。最近，我们发现激活的中性粒细胞通过释放髓过氧化物酶（MPO）抑制体外肺上皮细胞的核苷酸切除修复（NER）。为了评估中性粒细胞对体内NER的影响，向小鼠气管内滴注脂多糖（LPS）（20 μ g），引起急性肺部炎症和相关的中性粒细胞流入气道。暴露后三天，在肺组织匀浆中评估表型NER能力。LPS暴露抑制肺NER接近50%。这一发现得到了NER相关基因Xpa和Xpf下调的证实。为了进一步引出中性粒细胞和MPO在该过程中的作用，我们利用MPO缺陷小鼠以及通过抗体处理耗尽循环中性粒细胞的小鼠。LPS诱导的肺NER抑制不受Mpo（-/-）或循环中性粒细胞耗竭的影响。这与我们以前的体外观察结果形成对比，表明急性给药LPS后肺NER的抑制不完全由中性粒细胞和/或MPO介导。总之，这些数据表明，LPS诱导的肺部炎症与小鼠肺中NER功能的降低相关。
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 mu g), 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 similar to 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.