Together, these data reveal that SMPD3 expression and nSMase2 protein staining are enriched in COPD specimens, and, in some cases, expression was strongly induced concomitant with IL1RL1 and Muc5AC. nSMase2 and CD9 staining in proximity to cells exhibiting cytoplasmic and/or vesicular IL-33 staining patterns suggests the appropriate machinery is in place to facilitate secretion of IL-33–exosome complexes into the airway lumen and interstitium. Here, IL1RL1 is linked to chronic obstructive pulmonary disease.