• Samir Rustam, Yang Hu, Seyed Babak Mahjour, Andre F Rendeiro, Hiranmayi Ravichandran, Andreacarola Urso, Frank D'Ovidio, Fernando J Martinez, Nasser K Altorki, Bradley Richmond, Vasiliy Polosukhin, Jonathan A Kropski, Timothy S Blackwell, Scott H Randell, Olivier Elemento, and Renat Shaykhiev.
• Department of Medicine and.
• Am. J. Respir. Crit. Care Med. 2023 May 1; 207 (9): 117111821171-1182.

AbstractRationale: Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown. Objectives: To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin. Methods: 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-liquid interface model. Measurements and Main Results: The atlas of cellular heterogeneity along the proximal-distal 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-γ 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-γ. Conclusions: 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.

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