RATIONALE: Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. WNT/β-catenin signaling is reduced in COPD, however, the mechanisms thereof, specifically the role of WNT receptors Frizzled (FZD), remains unexplored. OBJECTIVE: To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD. METHODS: FZD receptor expression was analyzed in lung homogenates and primary alveolar epithelial type II (ATII) cells of never-smokers, smokers, and COPD patients, as well as two experimental emphysema models by qRT-PCR, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on WNT/β-catenin signaling and FZD4 function were investigated in primary ATII cells and cell lines. Gain- and loss-of-function approaches were applied to determine the effects of increased/decreased FZD4 expression on alveolar epithelial cell viability, wound repair, and elastogenesis. MEASUREMENTS AND MAIN RESULTS: FZD4 receptor expression was reduced in human and experimental COPD lung tissues as well as primary human ATII cells from COPD patients. Cigarette smoke exposure downregulated FZD4 expression in vitro and in vivo, along with reduced WNT target gene expression. Inhibition of FZD4 decreased WNT/β-catenin activity and epithelial cell proliferation, and interfered with ATII to ATI cell trans-differentiation, whereas FZD4 overexpression augmented WNT/β-catenin signaling and epithelial cell proliferation. Moreover, FZD4 overexpression rescued the cigarette smoke-induced decrease in elastin expression. CONCLUSIONS: Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity. Thus, FZD4 represents a potential therapeutic target for COPD.