A cute lung injury (ALI) and its most severe manifestation, ARDS, are characterized by an initial inhomogeneous infl ammatory reaction or epithelial injury that is followed by fi broblast proliferation and extracellular matrix (ECM) accumulation. 1,2 Mechanical ventilation is required for life support in patients with ARDS; however, the potential for overdistension of the healthy parts of the lungs is great. Ventilatorinduced lung injury (VILI) is characterized by noncardiogenic pulmonary edema; release of infl ammatory cytokines; infl ux of neutrophils; and increased message for the ECM proteins , including proteoglycans. 3,4 High tidal volume (V t ) mechanical ventilation can lead to the production of infl ammatory cytokines, including tumor necrosis factor-a , IL-1 b , macrophage infl ammatory protein (MIP)-2, and transforming growth factor-b 1 (TGF-b 1 ). 5,6 Chemokines are expressed in both the acute infl ammatory response and the subsequent wound remodeling after lung injury. Previous studies demonstrated that MIP-2 induces neovascularization and promotes angiogenesis during VILI. 5,7 As a major profi brogenic Methods: Male C57BL/6 mice (either wild type or lumican null) aged 3 months and weighing between 25 and 30 g were exposed to low V T (6 mL/kg) or high V T (30 mL/kg) mechanical ventilation with room air for 2 to 8 h. Nonventilated mice were used as control subjects. Results: We found that high V T mechanical ventilation increased microvascular permeability, neutrophil infl ux, production of free radicals, MIP-2 and TGF-b 1 proteins, positive staining of a -smooth muscle actin and S100A4/fi broblast-specifi c protein-1, Masson trichrome staining and extracellular collagen, and activation of lumican and ERK1/2 in wild-type mice. Decreased staining of the epithelial marker E-cadherin was also observed. Mechanical stretch-augmented EMT was attenuated with lumican-defi cient mice and pharmacologic inhibition of ERK1/2 activity by PD98059. Conclusions: The data suggest that lumican promotes high V T mechanical ventilation-induced lung injury and EMT through the activation of the ERK1/2 pathway.