Airway epithelial barrier dysfunction is frequently observed in chronic obstructive pulmonary disease(COPD). Adherens junction protein E-cadherin is critical in maintaining the structural and immunological airway epithelial barrier in COPD. Previous findings have shown that airway epithelial expression of E-cadherin is lower in lung tissue from COPD patients than non-COPD controls. We here asked whether epithelial junctional proteins are dysregulated in COPD-derived airway epithelium and what the functional consequences are of E-cadherin downregulation for cigarette smoke-induced airway epithelial damage, repair and inflammatory responses. We assessed junctional protein E-cadherin and ZO-1 expression in primary airway epithelial cells(AECs) derived from COPD and non-COPD donors.16HBE E-cadherin heterozygous cells(CDH1+/-) were generated using CRISPR-Cas9. Cells were exposed to cigarette smoke extract (CSE) followed by wounding by electroporation, ELISA and qPCR to assess mRNA expression of pro-inflammatory mediators. We observed lower expression of E-cadherin and ZO-1 in AECs derived from COPD donors. CDH1+/- resulted in delocalization of ZO-1.CSE exposure induced prolonged barrier dysfunction in CDH1+/-, as well as impaired repair upon wounding. In addition, either baseline or CSE-induced expression of CXCL8, IL-1A, GM-CSF and TSLP were higher in CDH1+/-. In conclusion, reduced E-cadherin result in enhanced release of pro-inflammatory mediators, prolonged barrier dysfunction and impaired repair response. Thus, the lower levels of E-cadherin may constitute a crucial step in cigarette smoke-induced epithelial abnormalities that may contribute to the development of COPD.