靶向弹性蛋白衍生肽逆转慢性阻塞性肺疾病肺泡上皮功能障碍
Targeting Elastin-Derived Peptides Reverses Alveolar Epithelial Dysfunction in Chronic Obstructive Pulmonary Disease.
摘要(中文译文)
慢性阻塞性肺疾病（COPD）以进行性肺泡破坏和再生缺陷为特征，然而参与该过程的基质来源因子仍研究不足。我们研究了弹性蛋白衍生肽（EDPs）——香烟烟雾（CS）诱导的弹性蛋白降解过程中产生的生物活性片段——在肺泡上皮功能障碍中的作用。在COPD患者的肺组织及暴露于香烟烟雾的小鼠中，EDPs水平升高与弹性纤维破坏及肺泡2型（AT2）向肺泡1型（AT1）分化受损相关。这些观察结果得到了组织学分析、单细胞转录组图谱分析和基于类器官的功能实验的支持。在小鼠和人肺泡类器官中，香烟烟雾提取物和EDPs均抑制类器官生长并损害AT2向AT1分化。在机制上，EDPs暴露与TLR4/NF-κB信号通路激活及β-catenin活性降低相关，而药理学抑制TLR4可部分恢复肺泡上皮分化。值得注意的是，EDPs中和剂TB在类器官中部分挽救了AT2向AT1分化，并在体内减轻了肺气肿性损伤。总之，这些发现表明EDPs是COPD中肺泡再生失败的重要基质来源介质，并支持进一步评估以EDPs为靶点的干预作为促进肺泡修复的潜在策略。
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar destruction and defective regeneration, yet the matrix-derived factors contributing to this process remain poorly defined. We investigated the role of elastin-derived peptides (EDPs), bioactive fragments generated during cigarette smoke (CS)-induced elastin degradation, in alveolar epithelial dysfunction. In lung tissues from patients with COPD and in CS-exposed mice, elevated levels of EDPs were associated with elastic fiber disruption and impaired alveolar type 2 (AT2)-to-alveolar type 1 (AT1) differentiation. These observations were supported by histological analyses, single-cell transcriptomic profiling, and organoid-based functional assays. In mouse and human alveolar organoids, CS extract and EDPs each suppressed organoid growth and impaired AT2-to-AT1 differentiation. Mechanistically, EDPs exposure was associated with activation of TLR4/NF-κB signaling, and reduced β-catenin activity, whereas pharmacological inhibition of TLR4 partially restored alveolar epithelial differentiation. Notably, the EDPs-neutralizing agent TB partially rescued AT2-to-AT1 differentiation in organoids and alleviated emphysematous injury in vivo. Together, these findings identify EDPs as an important matrix-derived mediator of alveolar regenerative failure in COPD and support further evaluation of EDP-targeted intervention as a potential strategy for promoting alveolar repair.
如何引用
AMA
Huijuan Zhu, Yiling Zhao, Yingchao Qin, Wenfeng Huang, Jiarui Weng, Zihan Liu, et al. Targeting Elastin-Derived Peptides Reverses Alveolar Epithelial Dysfunction in Chronic Obstructive Pulmonary Disease.. MedComm. 2026; doi:10.1002/mco2.70889.
APA
Huijuan Zhu, Yiling Zhao, Yingchao Qin, Wenfeng Huang, Jiarui Weng, Zihan Liu, et al (2026). Targeting Elastin-Derived Peptides Reverses Alveolar Epithelial Dysfunction in Chronic Obstructive Pulmonary Disease.. MedComm. https://doi.org/10.1002/mco2.70889
GB/T 7714
Huijuan Zhu, Yiling Zhao, Yingchao Qin, Wenfeng Huang, Jiarui Weng, Zihan Liu, et al. Targeting Elastin-Derived Peptides Reverses Alveolar Epithelial Dysfunction in Chronic Obstructive Pulmonary Disease.[J]. MedComm, 2026 doi:10.1002/mco2.70889.
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