Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Front Immunol. 2023 Jan 10;13:1023553. doi: 10.3389/fimmu.2022.1023553. eCollection 2022.
Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT.
中性粒细胞胞外诱捕网可导致囊性纤维化和哮喘的肺部损伤，但具体机制尚不清楚。我们旨在了解人源 NET 对原代人支气管上皮细胞和人气道上皮细胞系屏障功能的影响。研究表明，NET 通过降低跨上皮电阻和增加旁细胞通量来破坏气道上皮屏障功能，部分原因是 NET 诱导的气道细胞凋亡。NET 选择性影响紧密连接基因 Claudin 4、8 和 11 的表达。暴露于 NET 的支气管上皮细胞显示 E-钙黏蛋白染色出现明显间隙，全长 E-钙黏蛋白蛋白减少，出现裂解的 E-钙黏蛋白肽。NET 用 α-1 抗胰蛋白酶（A1AT）预处理可抑制 NET 丝氨酸蛋白酶活性，限制 E-钙黏蛋白的裂解，减少支气管细胞凋亡并维持上皮完整性。总之，NET 通过支气管细胞死亡和 E-钙黏蛋白降解破坏人气道上皮屏障功能，而外源性 A1AT 可限制这一过程。
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