Reversal of Emphysema by Restoration of Pulmonary Endothelial Cells

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease that is associated with exposure to inhaled irritants such as cigarette smoke and environmental pollutants. COPD is marked by airway inflammation and emphysema, leading to airflow obstruction and respiratory failure. The pathway to the development of COPD is yet to be fully understood but long-term inflammation is thought to be one of the main drivers. The functional role of vascular endothelial cells (ECs) in organ regeneration and repair has previously been described but it is not clear if the main driver of COPD pathophysiology is endothelial dysfunction or the consequence of damaged alveolar surface area. Choi et al. (2021) recently published promising data in the Journal of Experimental Medicine testing the therapeutic potential of correcting endothelial dysfunction on pathophysiological consequences of COPD.

The role of EC biology in the development of COPD was studied through human tissue analysis and purified ECs from the elastase-induced murine model of emphysema. EC loss and dysfunction were hallmarks of diseased lungs harvested from elastase-treated mice. Disease phenotypes were rescued by intravenous delivery of 5 × 10⁵ healthy lung ECs at days 7 and 14. Increased levels of leucine-rich α-2-glycoprotein-1 (LRG1) were found in both human COPD tissue and the endothelium of elastase-treated mice. An EC-specific inducible gene deletion strategy was used to explore the role of LRG1 in the development of emphysema. Deletion of lrg1 protected mice from the development of COPD/emphysema following elastase treatment. These findings identified a potential therapeutic target in LRG1 and revealed the regenerative potential of intravenous delivery of healthy lung EC delivery to patients with COPD/emphysema.

Additionally, pulmonary function measurements from naïve and elastase-treated mice were measured using the flexiVent FX. The creation of a functional COPD/emphysema phenotype was validated through pulmonary function tests. Pulmonary function measurements showed reduced lung elastance and an increased inspiratory capacity following elastase treatment. Following intravenous EC delivery, treated mice had improved lung function with reduced inspiratory capacity and an increase in lung elastance compared with untreated mice. Pulmonary function tests revealed that intravenous delivery of healthy ECs rescued the lung phenotype.

These researchers highlighted the importance of ECs to the pathogenesis of COPD/emphysema in human tissue. Disease states showed significant EC loss and alveolar destruction that could be rescued by intravenous delivery of healthy lung endothelial cells or deletion of Lrg1. Targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway set forth a new potential strategy for the treatment of COPD

Reference

Reversal of emphysema by restoration of pulmonary endothelial cells. (2021). Hisata, S., et al. Journal of Experimental Medicine, 216(8): e20200938