Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis
| Autor: | Michael C. Ostrowski, Carmen Z. Cantemir-Stone, Gerard J. Nuovo, Mohamed Kabbout, Charles L. Hitchcock, Sara N. Fischer, Clay B. Marsh, Christopher P. Baran, Sara McMaken, Christie A. Newland, Benjamin D. Bringardner, Gary Phillips |
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| Rok vydání: | 2011 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male Pathology medicine.medical_specialty Pulmonary Fibrosis Clinical Biochemistry Gene Expression Mice Transgenic Biology Bleomycin Collagen Type I Proto-Oncogene Protein c-ets-2 Extracellular matrix chemistry.chemical_compound Idiopathic pulmonary fibrosis Collagen Type III Mice Pulmonary fibrosis medicine Animals Humans Phosphorylation Fibroblast Molecular Biology Lung Cells Cultured Connective Tissue Growth Factor Cell Biology Pneumonia Articles Fibroblasts medicine.disease Actins medicine.anatomical_structure chemistry Type I collagen |
| Zdroj: | American journal of respiratory cell and molecular biology. 45(5) |
| ISSN: | 1535-4989 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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