Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation
Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation
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DOI：
10.1074/jbc.m110.135194
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发表时间：
2010-08-20
影响因子：
4.8
通讯作者：
Forteza, Rosanna Malbran
中科院分区：
文献类型：
--
作者：
Monzon, Maria E.;Fregien, Nevis;Forteza, Rosanna Malbran
透明质酸酶2（Hyal 2）是一种透明质酸（HA）降解酶，存在于细胞内或/和通过糖基磷脂酰肌醇（GPI）锚定在质膜上。正常人支气管上皮细胞（NHBE）生长在空气-液体界面（ALI），PI特异性磷脂酶C（PIPLC）处理，表现出增加的Hyal活性的分泌物和减少的蛋白质和活性的顶端膜，确认GPI锚定的Hyal 2在NHBE细胞中表达，它仍然是活跃的可溶性形式。我们已经报道，HA降解介导的活性氧（ROS）在人体气道。在这里，我们发现ROS增加NHBE细胞中Hyal 2的表达和活性，并且p38 MAPK信号通路参与了这种效应。通过使用表达慢病毒的小干扰RNA（siRNA）证实Hyal 2诱导。这些体外研究结果与吸烟者体内相关，其中上皮中Hyal 2免疫反应性增加与HA水平增加和支气管分泌物中低分子量HA物质的出现相关。总之，这项工作提供了ROS诱导Hyal 2的证据，表明Hyal 2可能是在与氧化应激相关的炎症条件下观察到的气道腔中持续HA片段化的原因。
Hyaluronidase 2 (Hyal2) is a hyaluronan (HA)-degrading enzyme found intracellularly or/and anchored to the plasma membrane through glycosylphosphatidylinositol (GPI). Normal human bronchial epithelial cells (NHBE) grown at the air-liquid interphase (ALI), treated with PI-specific phospholipase C (PIPLC), exhibited increased Hyal activity in secretions and decreased protein and activity on the apical membrane, confirming that GPI-anchored Hyal2 is expressed in NHBE cells and it remains active in its soluble form. We have reported that HA degradation was mediated by reactive oxygen species (ROS) in human airways. Here we show that ROS increase Hyal2 expression and activity in NHBE cells and that the p38MAPK signaling pathway is involved in this effect. Hyal2 induction was confirmed by using small interfering RNA (siRNA) expressing lentivirus. These in vitro findings correlated in vivo with smokers, where increased Hyal2 immunoreactivity in the epithelium was associated with augmented levels of HA and the appearance of low molecular mass HA species in bronchial secretions. In summary, this work provides evidence that ROS induce Hyal2, suggesting that Hyal2 is likely responsible for the sustained HA fragmentation in the airway lumen observed in inflammatory conditions associated with oxidative stress.