COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors.

Introduction: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised.
Methods: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation.
Results: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC ⁺ ) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub ⁺ ), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5 ⁺ ( P =0.018) and LAMB3 ⁺ ( P =0.050) expression, as well as a significant activation of Wnt-specific ( P =0.014) and Notch-specific ( P =0.021) genes, especially in precursors of suprabasal and secretory cells.
Conclusion: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.
Competing Interests: Competing interests: None declared.
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