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An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

¹ International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; ² Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and ³ Lung Biology Center, University of California at San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Eric S. White, M.D., Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail: docew{at}umich.edu

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 -smooth muscle actin (-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.

Measurements and Main 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 after bleomycin challenge, whereas wild-type controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer -SMA–expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-β and decreased lung fibroblast responsiveness to active TGF-β in vitro.

Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-β activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.

Key Words: fibrosis • fibronectin • TGF-β • myofibroblast

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Extra type III domain A (EDA) fibronectin is important in wound healing, where it is necessary for fibroblast activation. Pulmonary fibrosis reflects a dysregulated wound-healing response. What This Study Adds to the Field In this study, EDA fibronectin was necessary for pulmonary fibrosis to develop. In the absence of EDA fibronectin, fibroblasts were unable to differentiate into myofibroblasts or to fully activate latent transforming growth factor-β.