Feng Xu1, Dragoş M Vasilescu1, Daisuke Kinose1,2, Naoya Tanabe1,3, Kevin W Ng4, Harvey O Coxson1, Joel D Cooper5, Tillie-Louise Hackett1, Stijn E Verleden6, Bart M Vanaudenaerde7, Christopher S Stevenson8, Marc E Lenburg9, Avrum Spira9, Wan C Tan1, Don D Sin1, Raymond T Ng1,10, James C Hogg11. 1. The Centre for Heart Lung Innovation, The University of British Columbia, located at St Paul's Hospital, Vancouver, BC, Canada. 2. Division of Respiratory Medicine, Department of Medicine, Shiga University of Medical Science, Shiga, Japan. 3. Dept of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 4. The Francis Crick Institute, London, UK. 5. Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, PA, USA. 6. Laboratory of Respiratory Diseases, BREATHE, Dept of CHROMETA, KU Leuven, Leuven, Belgium. 7. Leuven Lung Transplant Unit, KU Leuven and UZ Gasthuisberg, Leuven, Belgium. 8. Lung Cancer Initiative at Johnson and Johnson, London, UK. 9. Division of Computational Biomedicine, Dept of Medicine, Boston University, Boston, MA, USA. 10. Dept of Computer Science, The University of British Columbia, Vancouver, BC, Canada. 11. The Centre for Heart Lung Innovation, The University of British Columbia, located at St Paul's Hospital, Vancouver, BC, Canada Jim.Hogg@hli.ubc.ca.
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.
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.