Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis.

Abstract

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.

• Authors: Christopher P Baran, Sara N Fischer, Gerard J Nuovo, Mohamed N Kabbout, Charles L Hitchcock, Benjamin D Bringardner, Sara McMaken, Christie A Newland, Carmen Z Cantemir-Stone, Gary S Phillips, Michael C Ostrowski, Clay B Marsh
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 45 Issue 5 Pg. 999-1006 (Nov 2011) ISSN: 1535-4989 [Electronic] United States
• PMID: 21562315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ACTA2 protein, human
• Actins
• CCN2 protein, human
• CCN2 protein, mouse
• Collagen Type I
• Collagen Type III
• ETS2 protein, human
• Ets2 protein, mouse
• Proto-Oncogene Protein c-ets-2
• alpha-smooth muscle actin, mouse
• Bleomycin
• Connective Tissue Growth Factor

Topics

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