Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
PLoS One. 2023 Dec 27;18(12):e0295684. doi: 10.1371/journal.pone.0295684. eCollection 2023.
Alveolar barrier dysfunction is one of the major pathophysiological changes in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In ALI/ARDS, tumor necrosis factor-alpha (TNFα) disrupts the barriers of alveolar epithelium and endothelium. Glucocorticoids (GCs) exert anti-inflammatory effects and ameliorate pulmonary edema in ALI/ARDS. However, the involvement of GCs in the restoration of alveolar epithelial barrier dysfunction has not been extensively studied. Here, we elucidated that dexamethasone (Dex) restored TNFα-induced alveolar epithelial barrier dysfunction in vitro using primary rat alveolar epithelial cells isolated from Sprague-Dawley rats. Moreover, Dex promoted the alveolar epithelial cell barrier integrity by initiating GC receptor-mediated signaling via the downregulation of myosin light chain kinase (MLCK) expression and the dephosphorylation of myosin light chain (MLC) 2. Further investigation revealed that Dex enhanced the expression of zonula occludens-1 (ZO-1), a tight junction-related protein, at intercellular junction sites. These findings suggest that GCs strengthen the integrity of the alveolar epithelial barrier in ALI/ARDS via the GR-MLCK-pMLC2 axis.
肺泡屏障功能障碍是急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）的主要病理生理变化之一。在 ALI/ARDS 中，肿瘤坏死因子-α（TNFα）破坏肺泡上皮和内皮的屏障。糖皮质激素（GCs）发挥抗炎作用，并改善 ALI/ARDS 中的肺水肿。然而，GCs 参与恢复肺泡上皮屏障功能障碍的情况尚未得到广泛研究。在这里，我们使用从 Sprague-Dawley 大鼠分离的原代大鼠肺泡上皮细胞，阐明了地塞米松（Dex）在体外恢复 TNFα诱导的肺泡上皮屏障功能障碍的作用。此外，Dex 通过下调肌球蛋白轻链激酶（MLCK）表达和肌球蛋白轻链（MLC）2 的去磷酸化，启动 GC 受体介导的信号转导，促进肺泡上皮细胞屏障完整性。进一步的研究表明，Dex 增强了细胞间连接位点紧密连接相关蛋白封闭蛋白-1（ZO-1）的表达。这些发现表明，GC 通过 GR-MLCK-pMLC2 轴增强 ALI/ARDS 中肺泡上皮屏障的完整性。
