Rationale: Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Objective: Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Methods: Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC), identified proximal and distal bronchioles in excised NCFB lungs. RNA-ISH and IHC assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial (HBE) cultures tested IL-1α/β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas/section area were increased in proximal, but not distal, bronchioles in NCFB vs control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated non-ectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1β-expressing macrophages. NCFB sterile sputum supernatants induced HBE MUC5B/MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, IL-1β-producing macrophages in mucus plugs, and downregulation of epithelial ciliogenesis genes. Conclusions: NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia.

中文翻译：

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近端和远端细支气管有助于非囊性纤维化支气管扩张 (NCFB) 的发病机制。

理由：非囊性纤维化支气管扩张（NCFB）可能起源于肺的细支气管区域。因此，需要表征 NCFB 细支气管的形态和分子特征。目的：检验以下假设：NCFB 是细支气管疾病的主要组成部分，表现为粘液堵塞和扩张。方法：通过组织学、RNA 原位杂交 (RNA-ISH) 和免疫组织化学 (IHC) 测量形态学标准和区域特异性上皮基因表达，识别切除的 NCFB 肺中的近端和远端细支气管。RNA-ISH 和 IHC 评估了细支气管粘液积累和粘蛋白基因表达。CRISPR-Cas9 介导的人支气管上皮 (HBE) 培养物中的 IL-1R1 敲除测试了 IL-1α/β 对粘蛋白产生的贡献。空间转录谱表征了 NCFB 远端细支气管基因表达。测量和主要结果：与对照肺相比，NCFB 中近端细支气管的细支气管周长和管腔面积/截面面积增加，但远端细支气管没有增加，表明近端细支气管扩张。在 NCFB 中，在患有疾病的切片中，在扩张的近端细支气管和相关的非扩张的远端细支气管中观察到粘液堵塞。MUC5AC 和 MUC5B 粘蛋白在 NCFB 近端细支气管中上调，而 MUC5B 在远端细支气管中选择性上调。细支气管粘液栓中充满了表达 IL-1β 的巨噬细胞。NCFB 无菌痰上清液诱导 HBE MUC5B/MUC5AC 表达，该表达被 IL-1R1 消融阻断 >80%。空间转录谱鉴定出与分泌细胞、缺氧、白细胞介素途径、粘液栓中产生 IL-1β 的巨噬细胞相关的基因上调，以及上皮纤毛发生基因的下调。结论：NCFB 表现出独特的近端和远端细支气管疾病。两个细支气管区域均表现出细支气管分泌细胞特征和粘液堵塞，但在粘蛋白基因调节和扩张方面有所不同。