We report for the first time to our knowledge that the increased NF-κB activation associated with the exuberant inflammatory response to CS in Cc16–/– mice directly contributed to their increased COPD-like disease, as delivering an NF-κB inhibitor to Cc16–/– mice reduced their exaggerated pulmonary inflammatory response and SAF, and rhCC16 reduced TNF-α–induced NF-κB activation in A549 NF-κB luciferase reporter cells in vitro. Here, SCGB1A1 is linked to chronic obstructive pulmonary disease.