STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation.
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-β, 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 α-smooth muscle actin, reduced collagen deposition. In addition, C-188-9 decreased the expression of epithelial injury markers, including hypoxia-inducible factor-1α (HIF-1α) and plasminogen activator inhibitor-1 (PAI-1). In vitro studies show that inhibition of STAT-3 decreased IL-6- and TGF-β-induced expression of multiple genes, including HIF-1α and PAI-1, in AECs. Furthermore, C-188-9 decreased fibroblast-to-myofibroblast differentiation. Finally, TGF-β 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.
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Mesias
M
Pedroza
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Thuy T
TT
Le
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Katherine
K
Lewis
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Harry
H
Karmouty-Quintana
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Sarah
S
To
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Anuh T
AT
George
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
Michael R
MR
Blackburn
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA.
David J
DJ
Tweardy
*Department of Medicine and Department of Infectious Disease, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston Medical School, Houston, Texas, USA skagarwa@bcm.edu.
Sandeep K
SK
Agarwal
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism*; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D001761:Bleomycin
STAT3; epithelial injury; fibrosis; myofibroblast