TY - JOUR
T1 - Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion
AU - Bagley, Dustin
AU - Russell, Tobias
AU - Ortiz-Zapater, Elena
AU - Stinson, Sally
AU - Fox, Kristina
AU - Redd, Paulina
AU - Joseph, Merry
AU - Deering-Rice, Cassandra
AU - Reilly, Christopher
AU - Parsons, Maddy
AU - Brightling, Christopher
AU - Rosenblatt, Jody
N1 - Funding Information:
We thank R. Krishnan and A. Locke for help with initial experiments and advice for our paper and G. Jenkins for introducing us to the Institute for Lung Health team. We thank S. Mitchell, C. Pardo Pastor, M. Redd, T. Zulueta-Coarasa, and D. Jackson for helpful comments on our manuscript. We are grateful to the vibrant asthma research community in London, which has provided invaluable insight into this disease. We thank the Huntsman Cancer Institute and King\u2019s College London Mouse Facilities; the Fluorescence Microscopy Facility at the Health Sciences Cores at the University of Utah; and the Huntsman Cancer Institute, Queen Mary University of London, King\u2019s College London, Imperial College London, University of Southampton Pathology Cores, and the Innovation Hub at King\u2019s College London and Confocal Imaging Core at University College London for tissue section handling and scanning. This study was supported by an American Asthma Foundation Award 16-0020, National Institute of Health R01GM102169, a Howard Hughes Faculty Scholar Award 55108560, and a Wellcome Investigator Award 221908/Z/20/Z to J.R. P30 CA042014 awarded to the Huntsman Cancer Institute core and an NCRR Shared Equipment grant no. 1S10RR024761-01 for the microscopy core supported this work. This study and research were funded by MRC MR/S009191/1 to M.P. and the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC) to C.B. The views expressed are those of the authors and are not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
We thank R. Krishnan and A. Locke for help with initial experiments and advice for our paper and G. Jenkins for introducing us to the Institute for Lung Health team. We thank S. Mitchell, C. Pardo Pastor, M. Redd, T. Zulueta-Coarasa, and D. Jackson for helpful comments on our manuscript. We are grateful to the vibrant asthma research community in London, which has provided invaluable insight into this disease. We thank the Huntsman Cancer Institute and King\u2019s College London Mouse Facilities; the Fluorescence Microscopy Facility at the Health Sciences Cores at the University of Utah; and the Huntsman Cancer Institute, Queen Mary University of London, King\u2019s College London, Imperial College London, University of Southampton Pathology Cores, and the Innovation Hub at King\u2019s College London and Confocal Imaging Core at University College London for tissue section handling and scanning. Funding: This study was supported by an American Asthma Foundation Award 16-0020, National Institute of Health R01GM102169, a Howard Hughes Faculty Scholar Award 55108560, and a Wellcome Investigator Award 221908/Z/20/Z to J.R. P30 CA042014 awarded to the Huntsman Cancer Institute core and an NCRR Shared Equipment grant no. 1S10RR024761-01 for the microscopy core supported this work. This study and research were funded by MRC MR/S009191/1 to M.P. and the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC) to C.B. The views expressed are those of the authors and are not necessarily those of the NIHR or the Department of Health and Social Care. Author contributions: J.R. designed experiments, interpreted and analyzed data, and wrote the manuscript. D.C.B., T.R., and K.F. designed experiments, interpreted data, and performed most live and fixed imaging experiments throughout the paper. P.F.R. and M.J. assisted with mouse priming, imaging, and quantification of imaging results of many of the experiments. C.R. and C.D.-R. consulted on experiments and pathology sections. E.O.-Z. provided HDM-primed mice and helped with the imaging of ex vivo slices. S.S. and C.B. provided lung slices from asthma patients. All authors edited the manuscript. Competing interests: C.B. reports grants and consultancy fees paid to his institution from Areteia, AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, Mologic, Regeneron Pharmaceuticals, Roche, and Sanofi, which are not related to the current manuscript. All other authors declare that they have no competing interests. Data and materials availability: All data are available in the main text or the supplementary materials. License information: Copyright \u00A9 2024 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www. science.org/about/science-licenses-journal-article-reuse. This article is subject to HHMI\u2019s Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the Author Accepted Manuscript (AAM) of this article can be made freely available under a CC BY 4.0 license immediately upon publication.
Publisher Copyright:
© 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024/4/4
Y1 - 2024/4/4
N2 - Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
AB - Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
KW - asthma
KW - extrusion
KW - epithelial
KW - bronchconstriction
KW - wound
UR - http://www.scopus.com/inward/record.url?scp=85190078294&partnerID=8YFLogxK
U2 - 10.1126/science.adk2758
DO - 10.1126/science.adk2758
M3 - Article
SN - 0036-8075
VL - 384
SP - 66
EP - 73
JO - Science
JF - Science
IS - 6691
M1 - 6691
ER -