Genotoxic effects of neutrophils and hypochlorous acid
Genotoxic effects of neutrophils and hypochlorous acid
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DOI：
10.1093/mutage/gep053
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发表时间：
2010-03-01
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;Knaapen, Ad M.;van Schooten, Frederik J.
慢性炎症已被认为是肺癌发病机制中的一个促成因素。在这个过程中，中性粒细胞释放的活性氧可能起着重要作用。本研究旨在探讨髓过氧化物酶（MPO）产生的主要嗜酸性氧化剂次氯酸（HOCl）对肺细胞DNA的损伤和致突变作用。HOCl在体外肺上皮A549细胞中具有致突变性，显示在生理浓度下显著诱导HPRT基因突变。我们研究了可能与HOCl诱导的致突变性相关的三种主要类型的DNA损伤。HOCl处理后，未发现单链DNA断裂和8-氧代-7，8-二氢-2 '-脱氧鸟苷增加。另一方面，HOCl导致3-（2-脱氧-β-D-异丙基-戊呋喃糖基）嘧啶并[1，2-α]嘌呤-10（3 H）-酮（M（1）dG）的形成显著增加，其可由丙二醛（MDA）或碱性丙烯醛形成。我们观察到增加MDA的形成后，暴露于HOCl的A549细胞，但不能排除碱丙烯醛的作用。与此一致，我们观察到，在气管内滴注脂多糖以诱导肺部炎症伴中性粒细胞流入的小鼠中，M（1）dG加合物水平增加了4倍。循环中性粒细胞的消耗显著降低肺MPO活性以及M（1）dG加合物水平，从而提供了中性粒细胞/HOCl和肺体内遗传毒性之间的因果关系。综上所述，这些数据表明，MPO在肺部炎症过程中催化形成HOCl应被视为嗜酸性粒细胞诱导的遗传毒性的重要来源。
Chronic inflammation has been recognized as a contributing factor in the pathogenesis of lung cancer. In this process, reactive oxygen species released by neutrophils may play an important role. The aim of the present study was to investigate the capacity of the major neutrophilic oxidant hypochlorous acid (HOCl), which is formed by myeloperoxidase (MPO), to induce DNA damage and mutagenicity in lung cells. HOCl was mutagenic in lung epithelial A549 cells in vitro, showing at physiological concentrations a significant induction of mutations in the HPRT gene. We studied three major types of DNA lesions that could be relevant for this HOCl-induced mutagenicity. Single strand DNA breakage and 8-oxo-7,8-dihydro-2'-deoxyguanosine were not found to be increased following HOCl treatment. On the other hand, HOCl caused a significant increase in the formation of 3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one (M(1)dG), which can be formed by either malondialdehyde (MDA) or base propenals. We observed an increased MDA formation upon exposure of A549 cells to HOCl, but a role of base propenals cannot be excluded. In line with this, we observed 4-fold increased M(1)dG adduct levels in mice that were intratracheally instilled with lipopolysaccharide to induce a pulmonary inflammation with neutrophil influx. Depletion of circulating neutrophils significantly reduced pulmonary MPO activity as well as M(1)dG adducts levels, thereby providing a causal link between neutrophils/HOCl and pulmonary genotoxicity in vivo. Taken together, these data indicate that MPO catalysed formation of HOCl during lung inflammation should be considered as a significant source of neutrophil-induced genotoxicity.