title: 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.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, 43210, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Baran
authors.forename: Sara N
authors.initials: SN
authors.lastname: Fischer
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Kabbout
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hitchcock
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bringardner
authors.forename: Sara
authors.initials: S
authors.lastname: McMaken
authors.forename: Christie A
authors.initials: CA
authors.lastname: Newland
authors.forename: Carmen Z
authors.initials: CZ
authors.lastname: Cantemir-Stone
authors.forename: Gary S
authors.initials: GS
authors.lastname: Phillips
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D024061:Collagen Type III / Q000096:biosynthesis / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D024042:Collagen Type I; D024061:Collagen Type III; C494069:ETS2 protein, human; C494070:Ets2 protein, mouse; D050787:Proto-Oncogene Protein c-ets-2; C544013:alpha-smooth muscle actin, mouse; D001761:Bleomycin; D055513:Connective Tissue Growth Factor