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This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of \u2265500 and &lt;1000\u2005\u00b5m, which we have termed a \u201chot spot\u201d. Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of<jats:italic>IFNG<\/jats:italic>signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01411-2021","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T16:13:02Z","timestamp":1634832782000},"page":"2101411","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD"],"prefix":"10.1183","volume":"59","author":[{"given":"Feng","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-4365","authenticated-orcid":false,"given":"Drago\u015f M.","family":"Vasilescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Kinose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7481-0212","authenticated-orcid":false,"given":"Naoya","family":"Tanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin W.","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey O.","family":"Coxson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel D.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tillie-Louise","family":"Hackett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn E.","family":"Verleden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart M.","family":"Vanaudenaerde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc E.","family":"Lenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avrum","family":"Spira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan C.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don D.","family":"Sin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond T.","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Hogg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"2024102102414344000_59.5.2101411.1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1152\/jappl.1967.22.3.395","article-title":"Resistance of central and peripheral airways measured by a retrograde catheter","volume":"22","author":"Macklem","year":"1967","journal-title":"J Appl Physiol"},{"key":"2024102102414344000_59.5.2101411.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196806202782501"},{"key":"2024102102414344000_59.5.2101411.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197006042822311"},{"key":"2024102102414344000_59.5.2101411.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197006042822302"},{"key":"2024102102414344000_59.5.2101411.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1106955"},{"key":"2024102102414344000_59.5.2101411.6","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S2213-2600(18)30196-6","article-title":"Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study","volume":"6","author":"Koo","year":"2018","journal-title":"Lancet Respir Med"},{"key":"2024102102414344000_59.5.2101411.7","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1164\/rccm.201602-0278OC","article-title":"Micro-computed tomography comparison of preterminal bronchioles in centrilobular and panlobular emphysema","volume":"195","author":"Tanabe","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"2024102102414344000_59.5.2101411.8","first-page":"894","article-title":"Loss of alveolar attachments in smokers. 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