Noncanonical WNT-5A is increased in murine models of COPD and contributes to emphysema development in vivo. (A) Immunoblots and quantification of WNT-5A and ABC in whole-lung homogenate of mice exposed to FA (n = 6) or CS (CS; n = 8) for 4 mo. (B) Expression Axin2 and KC (CXCL1) in whole-lung homogenate of mice exposed to FA (n = 6) or CS (n = 8) for 4 mo. (C) Immunoblots and quantification of WNT-5A expression in whole lung homogenate of mice 14 d after exposure to vehicle (PBS, n = 3) or elastase (n = 3). (D) Expression of Wnt-5A, Axin2, Nkd1, and Eln in whole-lung homogenate of mice 7 d after exposure to vehicle (PBS; n = 6) or elastase (n = 6–12). (A–D) *, P < 0.05; **, P < 0.01; ***, P < 0.001, unpaired Student’s t test. (E) Experimental setup to determine the impact of lung-specific WNT-5A overexpression on emphysema development. Animals had ad libitum access to drinking water containing 5% sucrose (solid line) or DOX (2 mg/ml) in 5% sucrose (dashed line). Animals were treated on day 0 with either elastase (PPE; 40 U/kg body weight) or vehicle control (PBS). Data are derived from two independent animal experiments. (F) Analysis of WNT-5A and tropoelastin at day 21 in whole-lung homogenate of SFTPC rtTA TetO-WNT-5A mice exposed to DOX or 5% sucrose in the drinking water and treated with elastase or vehicle control (n = 3–6 mice/group). *, P < 0.05; **, P < 0.01, determined by one-way ANOVA, followed by a Newman-Keuls multiple comparison test. (G) H&E-stained lung tissue sections. Bars: (left) 1 mm; (right) 100 µm. (H) Mean chord length as determined by quantitative morphometry (n = 6–9 animals per group). **, P < 0.01; ***, P < 0.001, compared with vehicle treatment with sucrose; ^###, P < 0.001 compared with vehicle treatment with DOX; ^$, P < 0.05, compared with elastase treatment with sucrose; determined by one-way ANOVA, followed by a Newman-Keuls multiple comparison test.