This study identified a resident population of stem/progenitor cells within the basal airway epithelium of the human lung. The clinical and translational relevance of this research was the observation that the number of resident airway epithelial stem cells is increased by 40 fold within the airways of asthmatic patients, compared to non-diseased airways. These data supported the current notion within the asthma research community, that the airway epithelium is dysregulated in its repair leading to airwayinflammation and remodeling.

This study demonstrated that basal airway epithelial cells are plastic with the capacity to undergo epithelial-mesenchymal transition. The increased number of basal cells within the airways of asthmatic patients results in an increased epithelial-mesenchymal transition response with expression of fibrotic markers and extracellular matrix in culture.

To understand the patholobiology of chronic lung diseases my lab has developed several imaging protocols to investigate the structural, cellular and extracellular matrix (ECM) environment of disease lesions using biobanked formalin-fixed-paraffin embedded (FFPE) samples. As example, we have developed protocols to image and quantify the 3-dimentional (3D) ultra-structure of the lung in FFPE samples using micro computed tomography (CT) imaging. This study demonstrated the use of non-linear optical microscopy (NLOM) to quantify the biochemical structure of collagen which is significantly deposited within remodeled asthmatic airways. This work showed that collagen is highly disorganized within the asthmatic airways due to lack of decorin expression by airway fibroblasts. The clinical and translational relevance of this research is that defective decorin production by airway fibroblasts offers a potential new therapeutic strategy for airway remodeling in asthma. Further, that NLOM probes with bronchoscopy opens the opportunity to monitor airway remodeling clinically in response to targeted therapeutic treatments.  This paper was highlighted with an accompanying editorial (Snelgrove RJ, et al., Zooming into the Matrix. AJRCCM. 2019) and featured as a journal club presentation from the American Thoracic Society (ATS).

This study demonstrated the use of non-linear optical microscopy (NLOM) to quantify the biochemical structure of collagen which is significantly deposited within remodeled asthmatic airways. This work showed that collagen is highly disorganized within the asthmatic airways due to lack of decorin expression by airway fibroblasts. The clinical and translational relevance of this research is that defective decorin production by airway fibroblasts offers a potential new therapeutic strategy for airway remodeling in asthma. Further, that NLOM probes with bronchoscopy opens the opportunity to monitor airway remodeling clinically in response to targeted therapeutic treatments.  This paper was highlighted with an accompanying editorial (Snelgrove RJ, et al., Zooming into the Matrix. AJRCCM. 2019) and featured as a journal club presentation from the American Thoracic Society (ATS).

Using microCT imaging of FFPE COPD lung samples we provided the first direct evidence that 41% of the smallest conducting airways, termed terminal bronchioles, and 57% of the alveolar surface area are irreversibly destroyed within the lungs of patients with the earliest stage of (Global Initiative for Obstructive Lung Disease (GOLD 1)) mild COPD. This study highlighted the inability of spirometry to detect early disease, as significant unrepairable damage of the lung has already occurred when a patient is diagnosed with mild (GOLD 1) COPD. Further, we demonstrated that in COPD lungs samples with a normal alveolar surface area that the small airways are lost prior to emphysematous destruction of alveolar tissue – a question that has been of much debate for the last 80 years. Lastly, we reported that patients at the late stages of disease (moderate to severe (GOLD 3 and 4) COPD) have lost 70-90% of their small airways. These data suggest that many large clinical trials investigating COPD treatments may have failed because the therapies were mostly tested on moderate to severe (GOLD 3 and 4) COPD patients, who would have limited small airways remaining for the therapeutics to act on. This study has been editorialized as identifying small airways as the ground zero of COPD pathology (Russell DW., et al.  COPD ground zero. The Lancet Respir Med. 2018), and has been used to spearhead a new Lancet Global Commission to identify new approaches to prevent, diagnose and treat early COPD (Dransfield M., et al. Towards eradication of chronic obstructive pulmonary disease: a Lancet Commission. 2019).

The concept that idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that obliterates  alveoli but spares the airways is widely accepted in the literature based on the observation that individuals with IPF can have much larger than normal airflows at low lung volumes. This study challenges the current thinking in IPF, as the report provides direct evidence that in regions of minimal parenchymal fibrosis there is already a 60% reduction in the number of small airways. These data indicate that small airways are an important feature of IPF, and a potential therapeutic target for future studies.