Journal Article

Transcription Factor ets-2 Plays an Important Role in the Pathogenesis of Pulmonary Fibrosis

Newland, Christie A., Fischer, Sara N., Phillips, Gary S., Baran, Christopher P., Bringardner, Benjamin D., Marsh, Clay B., Hitchcock, Charles L., McMaken, Sara, Ostrowski, Michael C., Nuovo, Gerard J., Kabbout, Mohamed N., Cantemir-Stone, Carmen Z.

2011

Overview

Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α-smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-β, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.

• Publisher: American Thoracic Society
• Subject: Actins - biosynthesis / Actins - genetics / Animals / Bleomycin - adverse effects / Cells, Cultured / Collagen Type I - biosynthesis / Collagen Type I - genetics / Collagen Type III - biosynthesis / Collagen Type III - genetics / Connective Tissue Growth Factor - biosynthesis / Connective Tissue Growth Factor - genetics / Fibroblasts - metabolism / Gene Expression / Humans / Lung - chemistry / Lung - pathology / Male / Mice / Mice, Transgenic / Phosphorylation / Pneumonia - chemically induced / Pneumonia - pathology / Proto-Oncogene Protein c-ets-2 - metabolism / Pulmonary Fibrosis - chemically induced / Pulmonary Fibrosis - metabolism / Pulmonary Fibrosis - pathology