Here, we apply syngeneic induced pluripotent stem cell-derived AT2s (iAT2s) and a novel mouse model featuring AT2-specific inducible human <i>SERPINA1</i> expression to interrogate the cell-instrinsic consequences of Z-AAT expression, validating findings in an independent dataset of human COPD lung tissue comparing ZZ to MM <i>SERPINA1</i> genotypes. Here, SERPINA1 is linked to chronic obstructive pulmonary disease.