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Investigating the nature of small airways disease and emphysema in mild & moderate chronic obstructive pulmonary disease

University of British Columbia

Chronic obstructive pulmonary disease (COPD) is an incurable and deadly lung disease, characterized by irreversible airflow limitation and chronic inflammation. Sadly, there has been a disheartening lack of new therapeutic approaches to counteract the progressive decline in lung function, which ultimately leads to disability and death. The majority of COPD patients in primary care have mild and moderate disease, but treatments and clinical trials have historically focused on more severe patients. In this thesis we used a novel approach that combined stereology, multi-resolution computed tomography (CT), and histology to provide the first direct evidence that 41% of terminal and 57% of transitional bronchioles are already lost in mild COPD patients. Additionally, we showed that this loss of small airways occurred in regions of the lung with normal parenchyma, suggesting that airway loss precedes emphysematous tissue destruction. Thus, in the remainder of the thesis we aimed to determine the structural, molecular and cellular alterations that occur in the remaining small airways, and how they might be targeted for therapeutic intervention in COPD. We demonstrate that the remaining terminal bronchioles in COPD patients have thickened walls due to deposition of fragmented fibrillar collagen, and progressively narrowed lumens with disease severity, due to loss of supporting radial tetherings (alveolar attachments). Using a systems biology approach to relate gene expression signatures to disease pathology, we identified a core set of 51 master regulators (transcription factors) that regulate the gene signatures associated with small airways disease and emphysema. Further, we identified mTOR inhibitors as potential novel therapeutics for COPD, and demonstrate the ability of mTOR inhibitors to block pathology associated inflammatory processes at the single cell level in immune cells from COPD patients. Lastly, using highly-multiplexed imaging mass cytometry we created the first single-cell atlas of the terminal bronchiole, demonstrating that the remaining terminal bronchioles of mild and moderate COPD patients have an activated immune response with increased cross-talk between innate and adaptive immune cells. Collectively, our data emphasize that early diagnosis and use of anti-inflammatory treatments early in the disease process will be required to alter small airway loss, and disease outcomes in COPD.

Text

2023-11-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/72404

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/