This study demonstrates that (i) WNT5A is expressed and localized in healthy lungs in response to MV in the absence of infection or toxics, (ii) the expression of WNT5A is dependent on the applied VT, (iii) activation of WNT5A and β-catenin are associated with up-regulation of downstream target genes, (such as Mmp7, cyclin D1, Vegf, and Axin2), and (iv) pulmonary fibrosis is induced very early during VILI. Here, MMP7 is linked to pulmonary fibrosis.