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Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice
Published on: January 16, 2015
The cellular and molecular determinants of emphysematous destruction in COPD
Masaru Suzuki1,2, Marc A Sze1, Joshua D Campbell3
1Centre for Heart Lung Innovation, St. Paul's Hospital, Departments of Medicine, and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Abstract:
The introduction of microCT has made it possible to show that the terminal bronchioles are narrowed and destroyed before the onset of emphysematous destruction in COPD. This report extends those observations to the cellular and molecular level in the centrilobular phenotype of emphysematous destruction in lungs donated by persons with very severe COPD (n = 4) treated by lung transplantation with unused donor lungs (n = 4) serving as controls. These lung specimens provided companion samples to those previously examined by microCT (n = 61) that we examined using quantitative histology (n = 61) and gene expression profiling (n = 48). The histological analysis showed that remodeling and destruction of the bronchiolar and alveolar tissue is associated with macrophage, CD4, CD8, and B cell infiltration with increased formation of tertiary lymphoid organs. Moreover, gene set enrichment analysis showed that genes known to be expressed by natural killer (NK), lymphoid tissue inducer (LTi), and innate lymphoid cell 1 (ILC1) cells, but not ILC2 or ILC3 cells, were enriched in the expression profiles associated with CD4, CD8, and B cell infiltration. Based on these findings, we postulate that the centrilobular phenotype of emphysematous destruction COPD is driven by a Th1 response activated by infiltrating ILC1, NK, and LTi cells.
Insights
Chronic obstructive pulmonary disease (COPD) involves airway destruction driven by immune cells. This study reveals that innate lymphoid cells (ILCs) and natural killer (NK) cells activate a Th1 response, causing centrilobular emphysema in COPD patients.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cell Biology
Background:
- Micro-computed tomography (microCT) revealed terminal bronchiolar damage precedes emphysema in COPD.
- Understanding the cellular and molecular drivers of COPD pathogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying the centrilobular phenotype of emphysematous destruction in severe COPD.
- To identify the immune cell populations and pathways involved in COPD-related lung tissue remodeling and destruction.
Main Methods:
- Quantitative histology and gene expression profiling were performed on lung tissue from COPD patients and control donors.
- Lung specimens were analyzed to assess cellular infiltration and lymphoid tissue formation.
- Gene set enrichment analysis identified enriched gene expression patterns related to specific immune cell types.
Main Results:
- Histological analysis showed macrophage, CD4+, CD8+, and B cell infiltration, along with tertiary lymphoid organ formation, in remodeled and destroyed bronchiolar and alveolar tissue.
- Gene expression profiling revealed enrichment of genes associated with natural killer (NK), lymphoid tissue inducer (LTi), and innate lymphoid cell 1 (ILC1) cells.
- This enrichment correlated with CD4+, CD8+, and B cell infiltration, but not with ILC2 or ILC3 cells.
Conclusions:
- The centrilobular emphysema phenotype in COPD is associated with significant immune cell infiltration and lymphoid tissue formation.
- Innate lymphoid cells (ILC1, LTi) and NK cells appear to play a key role in driving the Th1 immune response implicated in COPD pathogenesis.
- These findings suggest a potential therapeutic target for COPD by modulating the Th1 response mediated by these specific immune cells.
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