Reversal of emphysema by restoration of pulmonary endothelial cells

Shu Hisata, Alexandra C. Racanelli, Pouneh Kermani, Ryan Schreiner, Sean Houghton, Brisa Palikuqi, Balvir Kunar, Aiyuan Zhou, Keith McConn, Allyson Capili, David Redmond, Daniel J. Nolan, Michael Ginsberg, Bi Sen Ding, Fernando J. Martinez, Joseph M. Scandura, Suzanne M. Cloonan, Shahin Rafii, Augustine M.K. Choi

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/ emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich α-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.

Original languageEnglish (US)
Article numbere20200938
JournalJournal of Experimental Medicine
Volume218
Issue number8
DOIs
StatePublished - Jul 21 2021

ASJC Scopus subject areas

  • Medicine(all)

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