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The cellular basis of these structural changes remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To identify biological changes in pre-TBs\/TBs in COPD at single-cell resolution and determine their cellular origin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs\/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air\u2013liquid interface model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>The atlas of cellular heterogeneity along the proximal\u2013distal axis of the human lung was assembled and identified region-specific cellular states, including SCGB3A2+ SFTPB+ terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs\/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8+ T cells normally enriched in proximal airways, and augmented IFN-\u03b3 signaling. Basal cells residing in pre-TBs\/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-\u03b3.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Altered maintenance of the unique cellular organization of pre-TBs\/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202207-1384oc","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T17:08:45Z","timestamp":1676567325000},"page":"1171-1182","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":92,"title":["A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasser K.","family":"Altorki","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6200-5235","authenticated-orcid":false,"given":"Bradley","family":"Richmond","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical Center, Nashville, Tennessee"},{"name":"Department of Medicine, Vanderbilt University, Nashville, Tennessee; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliy","family":"Polosukhin","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Kropski","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical 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