RATIONALE: Tissue fibrosis is considered a dysregulated wound healing response. Fibronectin containing Extra Type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen. OBJECTIVES: To investigate the role of EDA-containing fibronectin in lung fibrogenesis. METHODS: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and -SMA expression. Mice lacking the EDA domain of fibronectin and their wild type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes. RESULTS: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and -SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days following bleomycin challenge, whereas wild-type controls developed the expected increase in total lung collagen. Histological analysis of EDA-null lungs following bleomycin showed less collagen and fewer -SMA-expressing myofibroblasts compared to that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor- and decreased lung fibroblast responsiveness to active transforming growth factor- in vitro. CONCLUSIONS: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through transforming growth factor- activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.