SERPINA1 and alpha-1-antitrypsin (AAT) are expressed in human alveolar type 2 cells (AT2s). (A-F) Peripheral human lung samples from 11 donors (4 wild-type “MM” COPD, 2 patients with alpha-1 antitrypsin deficiency [AATD] homozygous for the Z mutation [ZZ-AATD], and 5 healthy controls without chronic lung disease) were dissociated, CD45-reduced, and profiled by single-cell RNA sequencing. (A) Uniform manifold approximation and projection (UMAP) of peripheral human lung samples profiled by scRNA-Seq, labeled by donor disease state. (B) UMAP annotated by cell identity. (C) Dot plot of pulmonary epithelial marker gene expression among pulmonary epithelial cell clusters. (D) Dot plot of immune cell marker gene expression among immune cell clusters. (E) Feature plot of SERPINA1 expression and distribution in UMAP. (F) Violin plot of SERPINA1 expression in AT2s and alveolar macrophages and split by disease state of donor (∗∗∗∗P < .0001, Wilcoxon rank-sum test). (G) Representative immunofluorescence images of AAT (magenta) and pro-surfactant protein C (pro-SFTPC) (green) in distal human lung tissue from wild-type COPD, ZZ-AATD, and control donors. (H) Quantification of percentage of AAT+/SFTPC+ cells relative to the total number of pro-SFTPC+ cells (∗P < .05, ∗∗P < .01, Kruskal-Wallis test). N = 15 donors (4 wild-type COPD, 8 ZZ-AATD, 3 control). (I) Representative immunofluorescence images of AAT (magenta) and CD68 (green) in distal human lung tissue from wild-type COPD, ZZ-AATD, and control donors. AT1 = alveolar type 1 cell; PNEC = pulmonary neuroendocrine cell; RASC = respiratory airway secretory cell.