Restoring Pulmonary Endothelial Cells Reverses Emphysema in Mice

By David Douglas

July 30, 2021

NEW YORK (Reuters Health) - Correcting endothelial dysfunction in both human tissue and an elastase-induced murine model of emphysema shows promise in stopping and reversing the course of the disease, according to an international group of researchers.

"Current treatments for COPD/emphysema are very limited in their effectiveness. Our goal was to get at the root of what causes the disease so that we can prevent or reverse it," co-first author Dr. Alexandra Racanelli told Reuters Health by email. "We found, in a preclinical study, that damage to the cells that line the blood vessels of the lungs is an important driver of COPD/emphysema, and that injecting healthy versions of these cells prevented development of the disease."

In a report in the Journal of Experimental Medicine, Dr. Racanelli of Weill Cornell Medicine and New York-Presbyterian in New York City and colleagues note that despite "tantalizing associations" in the literature, "it is not clear that endothelial dysfunction drives COPD pathophysiology or is simply the consequence of damaged alveolar surface area."

In tissue samples from patients with COPD, substantial loss of the endothelial cell (EC) signature reflected more advanced clinical disease, the investigators found. This loss also aligned with radiographical evidence of advanced emphysematous changes.

EC loss and dysfunction were also hallmarks of emphysematous lungs harvested from the elastase-treated mice. The team found that intravenous delivery of healthy lung ECs from genetically identical mice reversed these phenotypes.

"We also found," continued Dr. Racanelli, "that removing a specific molecule from the cells had a similar result." In particular the researchers observe that "Leucine-rich a-2-glycoprotein- 1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression." LRG1 upregulation, they note ,"directly correlated with severity of the COPD phenotype."

"Our findings, while still early-stage, suggest that we may eventually be able to restore lung health in COPD/emphysema patients using regenerative cell therapy or using precision medicine to develop a drug that blocks the target molecule in the cells," concluded Dr. Racanelli.

SOURCE: Journal of Experimental Medicine, online July 21, 2021.