Among epithelial cells and based on transcriptomic analyses, we identify a subpopulation of HHIP-expressing alveolar epithelial type II (AT2) cells that mediate COPD heritability and have aberrant expression of metabolic, antioxidant, and cellular stress response genes in COPD, including reduced expression of the cellular stress response gene NUPR1. Our analyses of endothelial cells suggest capillary CXCL-motif chemokine signaling is an important cause of alveolar inflammation in COPD. The gene discussed is NUPR1; the disease is chronic obstructive pulmonary disease.