TY - JOUR
T1 - Reversal of emphysema by restoration of pulmonary endothelial cells
AU - Hisata, Shu
AU - Racanelli, Alexandra C.
AU - Kermani, Pouneh
AU - Schreiner, Ryan
AU - Houghton, Sean
AU - Palikuqi, Brisa
AU - Kunar, Balvir
AU - Zhou, Aiyuan
AU - McConn, Keith
AU - Capili, Allyson
AU - Redmond, David
AU - Nolan, Daniel J.
AU - Ginsberg, Michael
AU - Ding, Bi Sen
AU - Martinez, Fernando J.
AU - Scandura, Joseph M.
AU - Cloonan, Suzanne M.
AU - Rafii, Shahin
AU - Choi, Augustine M.K.
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01HL132198, P01Hl114501 (to A.M.K. Choi), R00 HL125899 (to S.M. Cloonan), 5T32HL134629 (to A.C. Racanelli), R35 HL150809, U01 AI 138329, RC2 DK11477 (to S. Rafii), CRIM (to M. Ginsberg and D.J. Nolan), T32 HD060600, and RFA#0906290930 (to B. Kunar), Leukemia and Lymphoma Society (to J.M. Scan-dura), the Cancer Research and Treatment Fund (to J.M. Scandura, P. Kermani), the Taub Foundation (to J.M. Scandura, P. Kermani), the National Heart, Lung, and Blood Institute (to J.M. Scandura, P. Kermani), the Daedalus Fund for Innovation from Weill Cornell Medicine, and the Tri-Institutional Stem Cell Initiatives (TRI-SCI 2019-029 to S. Rafii).
Funding Information:
equity holder of Angiocrine Bioscience. M. Ginsberg reported personal fees from Angiocrine Bioscience outside the submitted work; in addition, M. Ginsberg had a patent to 8,465,732 issued and a patent to 9,944,897 issued. In addition, M. Ginsberg is a current employee and equity holder of Angiocrine Bioscience. F.J. Martinez reported non-financial support from ProterrixBio, Nitto, Zambon; "other" from Afferent/Merck, Biogen, Veracyte, Prometic, Bridge Biotherapeutics, and Abbvie; grants from Gilead; and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Sunovion, Patara/Respivant, Bayer, Promedior/Roche, Teva, Col Behring, DevPro, IQVIA, Sanofi/ Regeneron, United Therapeutics, and Novartis outside the submitted work. S.M. Cloonan reported grants from National Institute of Health, National Heart, Blood and Lung Institute (NHLBI), and Science Foundation Ireland (SFI), and personal fees from Pharmacosmos outside the submitted work; in addition, S.M. Cloonan had a patent number 10,905,682 issued. S. Rafii reported non-financial support from Angiocrine Bioscience during the conduct of the study; non-financial support from Angiocrine Bioscience outside the submitted work; and had a patent to E4ORF1 Endothelial cell infusion for organ repair licensed (Angiocrine Bioscience). A.M.K. Choi is a cofounder and equity stock holder for Proterris, which develops therapeutic uses for carbon monoxide. A.M.K. Choi has a use patent on CO. Additionally, A.M.K. Choi has a patent in COPD. No other disclosures were reported.
Publisher Copyright:
© 2021 Hisata et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2021/7/21
Y1 - 2021/7/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85111553207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111553207&partnerID=8YFLogxK
U2 - 10.1084/jem.20200938
DO - 10.1084/jem.20200938
M3 - Article
C2 - 34287647
AN - SCOPUS:85111553207
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 8
M1 - e20200938
ER -