| First Author | Pedroza M | Year | 2016 |
| Journal | FASEB J | Volume | 30 |
| Issue | 1 | Pages | 129-40 |
| PubMed ID | 26324850 | Mgi Jnum | J:320784 |
| Mgi Id | MGI:6859200 | Doi | 10.1096/fj.15-273953 |
| Citation | Pedroza M, et al. (2016) STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. FASEB J 30(1):129-40 |
| abstractText | 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. |
