| 18096707 |
Muro AF, Moretti FA, Moore BB, Yan M, Atrasz RG, Wilke CA, Flaherty KR, Martinez FJ, Tsui JL, Sheppard D, Baralle FE, Toews GB, White ES: An essential role for fibronectin extra type III domain A in pulmonary fibrosis. J Invest Dermatol. 2008 Apr;128(4):855-66. Epub 2007 Oct 18.
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 alpha-smooth muscle actin (alpha-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 alpha-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 alpha-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)-beta and decreased lung fibroblast responsiveness to active TGF-beta in vitro. CONCLUSIONS: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-beta activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis. |
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