Publication
Title
The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD
Author
Abstract
Rationale Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. Methods Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. Results Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ⩾500 and <1000 μm, which we have termed a “hot spot”. Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. Interpretation The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.
Language
English
Source (journal)
The European respiratory journal / European Respiratory Society [Lausanne] - Copenhagen, 1988, currens
Publication
Copenhagen : 2021
ISSN
0903-1936 [print]
1399-3003 [online]
DOI
10.1183/13993003.01411-2021
Volume/pages
59 :5 (2022) , p. 1-12
Article Reference
2101411
ISI
000808266300001
Pubmed ID
34675046
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Research group
Publication type
Subject
External links
Web of Science
Record
Identifier
Creation 25.01.2024
Last edited 26.01.2024
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