RGD Reference Report - STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. - Rat Genome Database

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STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation.

Authors: Pedroza, M  Le, TT  Lewis, K  Karmouty-Quintana, H  To, S  George, AT  Blackburn, MR  Tweardy, DJ  Agarwal, SK 
Citation: Pedroza M, etal., FASEB J. 2016 Jan;30(1):129-40. doi: 10.1096/fj.15-273953. Epub 2015 Aug 31.
RGD ID: 11250698
Pubmed: PMID:26324850   (View Abstract at PubMed)
PMCID: PMC4684532   (View Article at PubMed Central)
DOI: DOI:10.1096/fj.15-273953   (Journal Full-text)

Lung fibrosis is the hallmark of the interstitial lung diseases. Alveolar epithelial cell (AEC) injury is a key step that contributes to a profibrotic microenvironment. Fibroblasts and myofibroblasts subsequently accumulate and deposit excessive extracellular matrix. In addition to TGF-beta, the IL-6 family of cytokines, which signal through STAT-3, may also contribute to lung fibrosis. In the current manuscript, the extent to which STAT-3 inhibition decreases lung fibrosis is investigated. Phosphorylated STAT-3 was elevated in lung biopsies from patients with idiopathic pulmonary fibrosis and bleomycin (BLM)-induced fibrotic murine lungs. C-188-9, a small molecule STAT-3 inhibitor, decreased pulmonary fibrosis in the intraperitoneal BLM model as assessed by arterial oxygen saturation (control, 84.4 +/- 1.3%; C-188-9, 94.4 +/- 0.8%), histology (Ashcroft score: untreated, 5.4 +/- 0.25; C-188-9, 3.3 +/- 0.14), and attenuated fibrotic markers such as diminished alpha-smooth muscle actin, reduced collagen deposition. In addition, C-188-9 decreased the expression of epithelial injury markers, including hypoxia-inducible factor-1alpha (HIF-1alpha) and plasminogen activator inhibitor-1 (PAI-1). In vitro studies show that inhibition of STAT-3 decreased IL-6- and TGF-beta-induced expression of multiple genes, including HIF-1alpha and PAI-1, in AECs. Furthermore, C-188-9 decreased fibroblast-to-myofibroblast differentiation. Finally, TGF-beta stimulation of lung fibroblasts resulted in SMAD2/SMAD3-dependent phosphorylation of STAT-3. These findings demonstrate that STAT-3 contributes to the development of lung fibrosis and suggest that STAT-3 may be a therapeutic target in pulmonary fibrosis.




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