Oxidative stress is a hallmark of numerous airway diseases, contributing to extensive cell and tissue damage. Cell membranes and the airway mucosal lining are rich in phospholipids that are particularly susceptible to oxidative attack, producing bioactive molecules including oxidized phosphatidylcholines (OxPC). With the recent discovery of elevated OxPC in asthmatic patients after allergen challenge, we hypothesized that OxPC directly contribute to disease by inducing airway epithelial cell dysfunction. We found that OxPC induced concentration-dependent cell stress and loss of viability in BEAS-2B and Calu-3 cell lines and primary human epithelial cells. These responses corresponded with significant epithelial barrier dysfunction, which was further compounded when combining OxPC with an epithelial wound. OxPC inhibited DNA synthesis and migration required to re-establish barrier function, but cells recovered if OxPC were washed off soon after treatment. OxPC induced generation of reactive oxygen species, lipid peroxidation and mitochondrial dysfunction, raising the possibility that OxPC cause pathological lipid metabolism in a self-propagating cycle. The oxidative stress induced by OxPC could not be abrogated by putative OxPC receptor blockers, but partial recovery of barrier function, proliferation and lipid peroxidation could be achieved with the antioxidant n-acetyl cysteine. In summary, we have identified OxPC as a group of bioactive molecules that significantly impair multiple facets of epithelial cell function, consistent with pathological features of asthma. Further characterisation of the mechanisms by which OxPC affect epithelial cells could yield new insights into how oxidative stress contributes to the pathogenesis of airway disease.

中文翻译：

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氧化磷脂酰胆碱诱导气道上皮细胞的多种功能缺陷

氧化应激是许多气道疾病的标志，会导致广泛的细胞和组织损伤。细胞膜和气道粘膜内衬富含磷脂，特别容易受到氧化攻击，产生包括氧化磷脂酰胆碱 (OxPC) 在内的生物活性分子。随着最近发现过敏原激发后哮喘患者 OxPC 升高，我们假设 OxPC 通过诱导气道上皮细胞功能障碍直接导致疾病。我们发现 OxPC 在 BEAS-2B 和 Calu-3 细胞系和原代人类上皮细胞中诱导浓度依赖性细胞应激和活力丧失。这些反应与显着的上皮屏障功能障碍相对应，当 OxPC 与上皮伤口相结合时，这种情况会进一步复杂化。OxPC 抑制了重建屏障功能所需的 DNA 合成和迁移，但如果 OxPC 在处理后很快被洗掉，细胞就会恢复。OxPC 诱导活性氧的产生、脂质过氧化和线粒体功能障碍，增加了 OxPC 在自我繁殖循环中引起病理性脂质代谢的可能性。由 OxPC 诱导的氧化应激不能被推定的 OxPC 受体阻滞剂消除，但可以通过抗氧化剂 n​​-乙酰半胱氨酸实现屏障功能、增殖和脂质过氧化的部分恢复。总之，我们已将 OxPC 确定为一组生物活性分子，可显着损害上皮细胞功能的多个方面，与哮喘的病理特征一致。