High-mobility group box-1 increases epithelial sodium channel activity and inflammation via the receptor for advanced glycation end products.
High-mobility group box-1 increases epithelial sodium channel activity and inflammation via the receptor for advanced glycation end products.
复制标题
高迁移率 group box-1 通过晚期糖基化终产物受体增加上皮钠通道活性和炎症。
DOI：
10.1152/ajpcell.00291.2019
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Helms,MyN
中科院分区：
文献类型：
--
作者：
Grant,GarettJ;Liou,TheodoreG;Paine3rd,Robert;Helms,MyN
囊性纤维化（CF）肺部疾病持续存在，并对许多患者造成生命限制。高迁移率组盒-1蛋白（HMGB-1）水平升高和上皮钠通道过度活跃（ENaC）是CF肺的标志性特征。本研究的目的是为了更好地了解HMGB-1信号和ENaC在CF气道细胞中的致病作用。我们假设HMGB-1与CF肺的气道炎症[通过向晚期糖基化终产物受体（RAGE）发出信号]和气道表面液体脱水（通过ENaC上调）有关。我们计算了在人HMGB-1肽（0.5 μg/mL）存在和不存在的情况下，正常和CF人小气道上皮细胞（SAEC）的等效短电流（Isc）和单通道ENaC打开概率（Po）。在正常saec中，HMGB-1升高了amiloile - sensitiveisland，使enacpo从0.15±0.03升高到0.28±0.04 （P< 0.01）。在CF saec中，enacpoinc由0.45±0.06增加到0.73±0.04 （P< 0.01）。1 μM FPS-ZM1 （RAGE抑制剂）预处理可减弱HMGB-1对正常和CF saec ENaC电流的影响。SAECs的共聚焦分析表明，ENaC功能障碍会影响细胞核大小和HMBG-1的定位。小鼠肺Masson三色标记显示，腹腔注射HMGB-1显著增加肺纤维化。hmgb -1处理小鼠支气管肺泡灌洗液中IL-1β、IL-10、IL-6、IL-27、IL-17A、IFN-β和粒细胞-巨噬细胞集落刺激因子均显著高于对照组（P< 0.05）。这些研究提出了一个新的模型，其中HMGB-1对RAGE的信号在CF肺ENaC功能障碍和炎症的持续发展中起重要作用。
Cystic fibrosis (CF) lung disease persists and remains life-limiting for many patients. Elevated high-mobility group box-1 protein (HMGB-1) levels and epithelial sodium channel hyperactivity (ENaC) are hallmark features of the CF lung. The objective of this study was to better understand the pathogenic role of HMGB-1 signaling and ENaC in CF airway cells. We hypothesize that HMGB-1 links airway inflammation [via signaling to the receptor for advanced glycation end products (RAGE)] and airway surface liquid dehydration (via upregulation of ENaC) in the CF lung. We calculated equivalent short-current (Isc) and single-channel ENaC open probability (Po) in normal and CF human small airway epithelial cells (SAEC) in the presence and absence of human HMGB-1 peptide (0.5 μg/mL). In normal SAECs, HMGB-1 increased amiloride-sensitiveIscand elevated ENaCPofrom 0.15 ± 0.03 to 0.28 ± 0.04 (P< 0.01). In CF SAECs, ENaCPoincreased from 0.45 ± 0.06 to 0.73 ± 0.04 (P< 0.01). Pretreatment with 1 μM FPS-ZM1 (a RAGE inhibitor) attenuated all HMGB-1 effects on ENaC current in normal and CF SAECs. Confocal analysis of SAECs indicates that nuclear size and HMBG-1 localization can be impacted by ENaC dysfunction. Masson’s trichrome labeling of mouse lung showed that intraperitoneally injected HMGB-1 significantly increased pulmonary fibrosis. Bronchoalveolar lavage fluid from HMGB-1-treated mice showed significant increases in IL-1β, IL-10, IL-6, IL-27, IL-17A, IFN-β, and granulocyte-macrophage colony-stimulating factor compared with vehicle-injected mice (P< 0.05). These studies put forth a new model in which HMGB-1 signaling to RAGE plays an important role in perpetuating ENaC dysfunction and inflammation in the CF lung.