Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease usually resulting from cigarette smoking (CS). Cigarette smoking induces oxidative stress, which causes inflammation and alveolar epithelial cell apoptosis and represents a compelling therapeutic target for COPD. Purified human platelet-derived exosome product (PEP) is endowed with antioxidant enzymes and immunomodulatory molecules that mediate tissue repair. In this study, a murine model of CS-induced emphysema was used to determine whether nebulized PEP can influence the development of CS-induced emphysema through the mitigation of oxidative stress and inflammation in the lung. Nebulization of PEP effectively delivered the PEP vesicles into the alveolar region, with evidence of their uptake by type I and type II alveolar epithelial cells and macrophages. Lung function testing and morphometric assessment showed a significant attenuation of CS-induced emphysema in mice treated with nebulized PEP thrice weekly for 4 weeks. Whole lung immuno-oncology RNA sequencing analysis revealed that PEP suppressed several CS-induced cell injuries and inflammatory pathways. Validation of inflammatory cytokines and apoptotic protein expression on the lung tissue revealed that mice treated with PEP had significantly lower levels of S100A8/A9 expressing macrophages, higher levels of CD4+/FOXP3+ Treg cells, and reduced NF-κB activation, inflammatory cytokine production, and apoptotic proteins expression. Further validation using cell culture showed that pretreatment of alveolar epithelial cells with PEP significantly attenuated CS extract-induced apoptotic cell death. These data show that nebulization of exosomes like PEP can effectively deliver exosome cargo into the lung, mitigate CS-induced emphysema in mice, and suppress oxidative lung injury, inflammation, and apoptotic alveolar epithelial cell death.

中文翻译：

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雾化血小板源性细胞外囊泡可减轻慢性香烟烟雾引起的小鼠肺气肿

慢性阻塞性肺病（COPD）是一种常见的肺部疾病，通常由吸烟（CS）引起。吸烟会诱发氧化应激，从而引起炎症和肺泡上皮细胞凋亡，是慢性阻塞性肺病的一个引人注目的治疗靶点。纯化的人血小板衍生外泌体产品 (PEP) 具有抗氧化酶和介导组织修复的免疫调节分子。在这项研究中，使用 CS 诱发的肺气肿小鼠模型来确定雾化 PEP 是否可以通过减轻肺部氧化应激和炎症来影响 CS 诱发的肺气肿的发展。 PEP 雾化有效地将 PEP 囊泡递送到肺泡区域，有证据表明它们被 I 型和 II 型肺泡上皮细胞和巨噬细胞吸收。肺功能测试和形态测量评估显示，每周三次雾化 PEP 治疗小鼠，持续 4 周，CS 引起的肺气肿显着减轻。全肺免疫肿瘤学 RNA 测序分析表明，PEP 抑制了多种 CS 诱导的细胞损伤和炎症途径。对肺组织炎症细胞因子和凋亡蛋白表达的验证表明，接受 PEP 治疗的小鼠表达 S100A8/A9 的巨噬细胞水平显着降低，CD4+/FOXP3+ Treg 细胞水平升高，NF-κB 激活、炎症细胞因子产生减少，凋亡蛋白的表达。使用细胞培养的进一步验证表明，用 PEP 预处理肺泡上皮细胞可显着减弱 CS 提取物诱导的细胞凋亡。这些数据表明，像 PEP 这样的外泌体雾化可以有效地将外泌体货物输送到肺部，减轻 CS 诱导的小鼠肺气肿，并抑制氧化性肺损伤、炎症和凋亡性肺泡上皮细胞死亡。