Background:Club cell secretory protein (CCSP) was found as a protective biomarker associated with annual decline in lung function. COPD progression results from an imbalance between injury and repair initially triggered by cigarette smoking. Objective:We investigated the effect of CCSP as a therapeutic strategy restoring the balance between injury and repair in COPD simultaneously validating an ex vivo air liquid interface (ALI) culture of human bronchial epithelial cells. Methods:Endobronchial biopsies (EBB) have been obtained from 13 COPD patients, 8 smokers and 8 control subjects. Morphometric analysis of the initial EBB has been performed. ALI cultures derived from the same EBB were exposed to cigarette smoke extract (CSE) with or without exogenous rhCCSP supplementation. CCSP and CXCL8 concentrations were assessed at steady state and after CSE exposure. Results:Morphometric analysis of the initial EBB showed increased cell density but decreased immunostaining of CCSP+ cells in COPD (p=0.03 vs. controls). At steady state, lower CCSP (p=0.04) and higher CXCL8 levels (p<.0001) were found in COPD ALI epithelium. Exogenous rhCCSP supplementation dampened CSE-induced CXCL8-release in COPD patients which returned to similar levels as smokers and controls (p=.0001). A negative correlation was found between CXCL8-release in ALI and CCSP+ cells density in initial biopsies (p=.0073). Conclusion:In vitro, rhCCSP exogenous supplementation can reverse CSE-induced CXCL8-release in COPD indicating a potential use of this strategy in vivo.