Injurious mechanical ventilation (MV) induces and amplifies lung injury, in part through Wnt/β-catenin signaling. Wnt-7a is required for normal lung epithelial barrier integrity but its role in the progression of VILI is unknown. Male (6-8 weeks) Wnt-7a knockout (KO) or wild type (WT) mice were subjected to MV with injurious (Vt 24 ml/kg; PEEP 0) strategy for 3hours. Lung mechanics and pulse oximetry were monitored. Terminal BAL and lung tissues harvesting was performed for semiquantitative lung injury scoring on H&E sections. Whole lung protein lysates were subjected to PAGE and immunoblotting for MAPK proteins, MKP-1, GSK-3β and β-catenin. Wnt-7a KO mice were significantly protected against injurious MV (Cstat % of baseline at 3 hrs KO (n=5): 104.8±27.4% vs. WT (n=4): 69.1±20.8%; P＜0.05). Total BAL cell counts were comparable (KO: 7.9±2.1×104 vs. WT: 8.3±1.3×104 cell/ml, P=0.76). Lung injury scores (LIS) were lower in KO group than that of WT group (5.1±1.1 vs 6.3±0.7, P=0.07). There was similar significant induction of cytokine expression adjusted by tubulin between WT and KO mice. Whole lung activated β-catenin was lower and total GSK-3β expression were significantly increased in KO vs WT after injurious MV (0.36-fold, P=0.004 and 3-fold, P=0.01 respectively). pERK1/2 (4.7-fold, P＜0.01) expression was increased relative to total MAPK levels in KO lungs vs WT. In conclusion Wnt-7a is required for β-catenin dependent lung injury progression and deficiency is associated with β-catenin/GSK stabilization and ERK activation.