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

TitleTranscription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis
Publication TypeJournal Article
Year of Publication2011
AuthorsBaran CP, Fischer SN, Nuovo GJ, Kabbout MN, Hitchcock CL, Bringardner BD, McMaken S, Newland CA, Cantemir-Stone CZ, Phillips GS, Ostrowski MC, Marsh CB
JournalAm J Respir Cell Mol Biol
Volume45
Issue5
Pagination999-1006
Date Published2011 Nov
ISSN1535-4989
KeywordsActins, Animals, Bleomycin, Cells, Cultured, Collagen Type I, Collagen Type III, Connective Tissue Growth Factor, Fibroblasts, Gene Expression, Humans, Lung, Male, Mice, Mice, Transgenic, Phosphorylation, Pneumonia, Proto-Oncogene Protein c-ets-2, 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.

DOI10.1165/rcmb.2010-0490OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID21562315
PubMed Central IDPMC3262682
Grant ListR01 CA053271 / CA / NCI NIH HHS / United States
R01 HL067176 / HL / NHLBI NIH HHS / United States
R03 HL095431-01 / HL / NHLBI NIH HHS / United States