Reversal of emphysema by restoration of pulmonary endothelial cells

Chronic obstructive pulmonary disease (COPD) is a heterogenous disorder marked by small airway inflammation and distal airspace enlargement (emphysema) leading to progressive airflow obstruction and eventual respiratory failure. Current therapies are limited in their ability to halt the pathogenesis of COPD merely relieving symptoms of dyspnea and airflow limitation. Microvasculature dysfunction, an understudied area of investigation, is associated with the severity of COPD. However, it is not known if abnormal lung endothelium drives COPD pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of specialized pulmonary endothelial cells to lung pathogenesis in an elastase-induced murine model of COPD. Airspace disease was marked by aberrant endothelial cell loss and dysfunction, which was rescued by intravenous delivery of healthy lung endothelial cells. Airspace injury triggered regulation of a distinct module of maladaptive endothelial transcripts comprising lost endothelial cell function. Endothelial leucine-rich alpha-2-glycoprotein-1 (LRG1) was identified as a key driver of the emphysematous pathology and selective deletion of Lrg1 from endothelial cells rescued elastase-induced defects of pulmonary parenchymal destruction. Hence, targeting lung endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent novel therapeutic strategies of immense potential for the treatment of emphysema. Overall design: RNA sequencing of mouse lung endothelial cells after one and six months of whole body smoke compared to controls at room air. Expression profiling by high throughput sequencing data; Illumina HiSeq 4000 (Mus musculus).