The airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS. We retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls. Compared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE. The airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia.

中文翻译：

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急性呼吸窘迫综合征中的气道上皮损伤


气道上皮 （AE） 具有维持肺稳态的多种功能，其中包括确保足够的屏障功能、细胞分化和极化，以及通过聚合物免疫球蛋白受体 （pIgR） 主动运输免疫球蛋白 A （IgA），气道腔中的主要粘膜免疫球蛋白。ARDS 患者报道了气道的形态学变化，但其详细特征、对粘膜免疫的影响和致病机制仍不清楚。因此，本研究旨在评估 ARDS 患者远端气道的上皮改变。我们回顾性分析了来自 ARDS 患者和对照者的肺组织样本，以研究和量化小气道的结构和功能变化，使用多重荧光免疫染色和计算机辅助定量整个组织切片。此外，我们测量了前瞻性收集的 ARDS 患者和对照组的血清和支气管肺泡灌洗液 （BALF） 中的粘膜免疫标志物、IgA 和 pIgR 以及其他上皮标志物。与对照组相比，ARDS 的气道特征是上皮剥脱增加 （p = 0.0003） 和中性粒细胞弥漫性上皮浸润 （p = 0.0005）。多重荧光免疫染色的定量评估显示纤毛细胞丢失 （p = 0.0317），杯状细胞减少的趋势 （p = 0.056），细胞祖细胞 （基底细胞和俱乐部细胞） 没有变化，表明粘膜纤毛分化改变。在 ARDS 中也显示上皮通透性增加，紧密 （p < 0.0001） 和粘附 （p = 0.025） 连接蛋白显着减少。此外，我们观察到 pIgR 的表达显著降低 （p < 0.0001），表明粘膜 IgA 免疫受损。ARDS （均为 p < 0.0001） 以及其他肺源蛋白 （CC16、SP-D、sRAGE） 的血清分泌成分 （SC） 和 S-IgA 浓度增加。然而，它们的 BALF 浓度保持不变，表明气道和肺泡蛋白通过受损的 AE 溢出。ARDS 患者的气道上皮表现出多方面改变，导致粘膜纤毛分化改变、防御功能受损和肺蛋白血症通透性增加。