We have shown that a decrease in E-cadherin is causal to epithelial barrier dysfunction and alveolar destruction (Ghosh, B. et al. 2022). This encouraged us to look at strategies to make the available E-cadherin function better. Interestingly, we found, using SPIROMICS and COPDGene, that CDH1 has a single nucleotide polymorphism (SNP) in 100% linkage disequilibrium with a SNP in the FUT2 gene. This SNP modifies both protein function and secretor status and can ultimately result in no expression of the protein. Utilizing MALDI-TOF mass spectrometry we demonstrated that when E-cadherin is co-expressed with FUT2 there is increased FUT2-dependent fucosylation. In age and sex matched patient-derived human bronchial epithelia from healthy and COPD donors we found a marked decrease in both fucosylated proteins overall, seen in both immunofluorescence images and immunoblots, but also fucosylated E-cadherin isolated by immunoprecipitation. Our well-differentiated COPD epithelia show increased paracellular permeability as measured by FITC-dextran flux and decreased transepithelial electrical resistance (TEER). However, overexpression of FUT2 in COPD cells improves barrier integrity. Moreover, Fut2-/- mouse tracheal epithelial cells demonstrate significant barrier dysfunction compared to wild-type controls. While cigarette smoke (CS) injury disrupted the barrier integrity of wild-type epithelial cells, Fut2-/- epithelial cells saw little to no further injury. Human precision cut lung slices exposed to CS resulted in alveolar destruction, which was abrogated with FUT2 overexpression.  Our data shows that FUT2 has potential to serve as a novel therapeutic target against the progression of COPD.