氧化磷脂酰胆碱诱导气道上皮细胞多功能缺陷
2021/08/24
摘要
氧化应激是许多气道疾病的特征，导致广泛的细胞和组织损伤。细胞膜和气道粘膜衬里富含磷脂，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。近期发现哮喘患者在变应原激发后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。这些反应与显著的上皮屏障功能障碍相对应，当OxPC与上皮伤口结合时，这种功能障碍进一步加剧。OxPC抑制重建屏障功能所需的DNA合成和迁移，但如果处理后不久OxPC被洗掉，细胞就会恢复。OxPC诱导活性氧物种的产生、脂质过氧化和线粒体功能障碍，增加了OxPC在自我繁殖周期中引起病理性脂质代谢的可能性。OxPC诱导的氧化应激不能被假定的OxPC受体阻滞剂消除，但抗氧化剂n-乙酰半胱氨酸可以部分恢复屏障功能、增殖和脂质过氧化。总之，我们已经确定OxPC是一组生物活性分子，可显著损害上皮细胞功能的多个方面，与哮喘的病理特征一致。对OxPC影响上皮细胞的机制的进一步描述可以为氧化应激如何参与气道疾病的发病机制提供新的见解。
Oxidized Phosphatidylcholines Induce Multiple Functional Defects in Airway Epithelial Cells
Christopher D Pascoe, Neilloy Roy, Emily Turner-Brannen, Alexander Schultz, Jignesh Vaghasiya, Amir Ravandi, Andrew John Halayko, Adrian Robert West
Abstract
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.
氧化应激是许多气道疾病的特征，导致广泛的细胞和组织损伤。细胞膜和气道粘膜衬里富含磷脂，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。近期发现哮喘患者在变应原激发后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。这些反应与显著的上皮屏障功能障碍相对应，当OxPC与上皮伤口结合时，这种功能障碍进一步加剧。OxPC抑制重建屏障功能所需的DNA合成和迁移，但如果处理后不久OxPC被洗掉，细胞就会恢复。OxPC诱导活性氧物种的产生、脂质过氧化和线粒体功能障碍，增加了OxPC在自我繁殖周期中引起病理性脂质代谢的可能性。OxPC诱导的氧化应激不能被假定的OxPC受体阻滞剂消除，但抗氧化剂n-乙酰半胱氨酸可以部分恢复屏障功能、增殖和脂质过氧化。总之，我们已经确定OxPC是一组生物活性分子，可显著损害上皮细胞功能的多个方面，与哮喘的病理特征一致。对OxPC影响上皮细胞的机制的进一步描述可以为氧化应激如何参与气道疾病的发病机制提供新的见解。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Am J Physiol Lung Cell Mol Physiol. 2021 Aug 4. doi: 10.1152/ajplung.00539.2020.)
(Am J Physiol Lung Cell Mol Physiol. 2021 Aug 4. doi: 10.1152/ajplung.00539.2020.)
Oxidized Phosphatidylcholines Induce Multiple Functional Defects in Airway Epithelial Cells
Christopher D Pascoe, Neilloy Roy, Emily Turner-Brannen, Alexander Schultz, Jignesh Vaghasiya, Amir Ravandi, Andrew John Halayko, Adrian Robert West
Abstract
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.
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聚-L-精氨酸通过激活 mTORC1-STAT3 通路诱导气道上皮细胞中的 FGFBP1 促进哮喘血管生成
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