Stem Cell Research Unit, BioMedical Center, School of Health Sciences, University of Iceland, Reykjavík, Iceland.
Department of Laboratory Hematology, Landspitali-University Hospital, Reykjavík, Iceland.
ALTEX. 2020;37(4):545-560. doi: 10.14573/altex.2001271. Epub 2020 May 19.
Azithromycin (AZM) is a broad-spectrum antibiotic widely used to treat infections. AZM also has been shown to have anti-inflammatory and immunomodulatory functions unrelated to its antibacterial activity that contribute to the effectiveness of this drug in chronic respiratory diseases. The mechanisms behind these beneficial effects are not yet fully elucidated. We have previously shown that AZM enhances barrier integrity of bronchial epithelial cells and directs them towards epidermal differentiation. In this study, we analyzed the effect of AZM pre-treatment of human bronchial and alveolar derived cell lines on mechanical stress in a cyclical pressure air-liquid interface device (CPAD) that models the disruption of the epithelial barrier with increased inflammatory response in lung tissue, which is associated with ventilator-induced lung injury (VILI). Immunostaining and electron microscopy showed that barrier integrity of the epithelium was compromised by cyclically stressing the cells but maintained when cells had been pre-treated with AZM. Lamellar body formation was revealed in AZM pre-treated cells, possibly further supporting the barrier-enhancing effects. RNA sequencing showed that the inflammatory response was attenuated by AZM treatment before cyclical stress. YKL-40, an emerging inflammatory marker, increased both due to cyclical stress and upon AZM treatment. These data confirm the usefulness of the CPAD to model ventilator-induced lung injury and suggest that AZM has barrier protective and immunomodulatory effects, attenuating the inflammatory response during mechanical stress, and might therefore be lung protective during mechanical ventilation. The model could be used to assess further drug candidates that influence barrier integrity and modulate inflammatory response.
阿奇霉素（AZM）是一种广谱抗生素，广泛用于治疗感染。AZM 还具有与抗菌活性无关的抗炎和免疫调节功能，这有助于该药物在慢性呼吸道疾病中的疗效。这些有益作用的机制尚未完全阐明。我们之前已经表明，AZM 增强了支气管上皮细胞的屏障完整性，并促使它们向表皮分化。在这项研究中，我们分析了 AZM 预处理人支气管和肺泡衍生细胞系对周期性压力气液界面装置（CPAD）中机械应激的影响，该装置模拟了上皮屏障的破坏以及肺组织中炎症反应的增加，这与呼吸机引起的肺损伤（VILI）有关。免疫染色和电子显微镜显示，周期性地对细胞施加压力会破坏上皮细胞的屏障完整性，但当细胞用 AZM 预处理时，这种屏障完整性得以维持。在 AZM 预处理的细胞中发现了板层小体的形成，这可能进一步支持了屏障增强作用。RNA 测序显示，AZM 预处理可减轻周期性压力前的炎症反应。YKL-40 是一种新兴的炎症标志物，由于周期性压力和 AZM 处理而增加。这些数据证实了 CPAD 可用于模拟呼吸机引起的肺损伤，并表明 AZM 具有屏障保护和免疫调节作用，可减轻机械应激过程中的炎症反应，因此在机械通气期间可能具有肺保护作用。该模型可用于评估进一步影响屏障完整性和调节炎症反应的候选药物。
