| Autor: |
Asakura T; Marsico Lung Institute/Cystic Fibrosis Research Center.; Department of Clinical Medicine, Laboratory of Bioregulatory Medicine, Kitasato University School of Pharmacy, Tokyo, Japan.; Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.; Division of Pulmonary Medicine, Department of Medicine., Okuda K; Marsico Lung Institute/Cystic Fibrosis Research Center., Chen G; Marsico Lung Institute/Cystic Fibrosis Research Center., Dang H; Marsico Lung Institute/Cystic Fibrosis Research Center., Kato T; Marsico Lung Institute/Cystic Fibrosis Research Center., Mikami Y; Marsico Lung Institute/Cystic Fibrosis Research Center., Schworer SA; Marsico Lung Institute/Cystic Fibrosis Research Center., Gilmore RC; Marsico Lung Institute/Cystic Fibrosis Research Center., Radicioni G; Marsico Lung Institute/Cystic Fibrosis Research Center., Hawkins P; Marsico Lung Institute/Cystic Fibrosis Research Center., Barbosa Cardenas SM; Marsico Lung Institute/Cystic Fibrosis Research Center., Saito M; Marsico Lung Institute/Cystic Fibrosis Research Center., Cawley AM; Marsico Lung Institute/Cystic Fibrosis Research Center., De la Cruz G; Pathology Services Core, Lineberger Comprehensive Cancer Center, and., Chua M; Marsico Lung Institute/Cystic Fibrosis Research Center., Alexis NE; Center for Environmental Medicine, Asthma, and Lung Biology, Division of Allergy and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Masugi Y; Department of Pathology, and., Noone PG; Marsico Lung Institute/Cystic Fibrosis Research Center., Ribeiro CMP; Marsico Lung Institute/Cystic Fibrosis Research Center., Kesimer M; Marsico Lung Institute/Cystic Fibrosis Research Center., Olivier KN; Marsico Lung Institute/Cystic Fibrosis Research Center.; Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland., Hasegawa N; Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan; and., Randell SH; Marsico Lung Institute/Cystic Fibrosis Research Center., O'Neal WK; Marsico Lung Institute/Cystic Fibrosis Research Center., Boucher RC; Marsico Lung Institute/Cystic Fibrosis Research Center. |
| Abstrakt: |
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. Objectives: 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 and immunohistochemistry, identified proximal and distal bronchioles in excised NCFB lungs. RNA in situ hybridization and immunohistochemistry assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial cultures tested IL-1α and IL-1β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas per section area were increased in proximal, but not distal, bronchioles in NCFB versus control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated nonectatic 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 human bronchial epithelial MUC5B and MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, and 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. |
