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

Abstract

Lung fibrosis is the hallmark of the interstitial lung diseases. Alveolar epithelial cell (AEC) injury is akey 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.—Pedroza, M., Le, T. T., Lewis, K., Karmouty‐Quintana, H., To, S., George, A. T., Blackburn, M. R., Tweardy, D. J., Agarwal, S. K. STAT‐3 contributes to pulmonary fibrosis through epithelial injury and fibroblast‐myofibroblast differentiation. FASEB J. 30, 129‐140 (2016). http://www.fasebj.org

Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures

“…Immunohistochemical analysis revealed that both SERPINE1 and α-SMA at the tumor-advancing front of OSCCs were significantly associated with extracapsular spread of cervical lymph nodes, a prognostic marker of OSCC outcome, and the combination of α-SMA/SERPINE1 positivity was significantly associated with poor survival of OSCC patients [41]. Interestingly, C-188-9, a STAT-3 inhibitor, decreased pulmonary fibrosis and resulted in inhibition of fibroblast-to-myofibroblast differentiation and TGF-β-induced expression of multiple genes including SERPINE1 [42]. Another protein that may support the protumoral effects of CAFs on oral cancer cells is STC2, which we found to be upregulated in the secretome of CAFs and in TGF-β1-treated NOFs.…”

Mechanisms of carbon nanotube‐induced pulmonary fibrosis: a physicochemical characteristic perspective

“…STAT3 is implicated in cell growth and carcinogenesis, while STAT6 is responsible for promoting a more allergic phenotype. TGF-β1 treatment of lung myofibroblasts has been shown to activate STAT3 and promote proliferation adjacent of epithelial damage 113 . Either STAT dysregulation would result in an abnormal phenotype and could result in increased proliferation or exacerbation of fibrosis or asthma 33 .…”

Identification of periplakin as a major regulator of lung injury and repair in mice

“…Recent data also indicate that STAT3 contributes to the development of lung fibrosis as a regulator of TGF-β transcriptional activity (18 and Ppl -/-mouse lung ( Figure 7A). After bleomycin, P-STAT3 was increased from D3 to D14 in Ppl +/+ lungs, whereas only a transient and mild increase on D3 was noted in Ppl -/-lungs ( Figure 7A).…”

“…IHC experiments showed a delayed activation of Stat3 in AECs and less P-Stat3 in fibrotic areas in Ppl -/-mice. Stat3 activation has been implicated in the fibrotic lung in patients with IPF and in bleomycin-induced lung fibrosis in mice (18,43). Alterations in the inflammatory environment of the lung in Ppl -/-mice may have caused the decrease in STAT3 activation.…”

“…Alterations in the inflammatory environment of the lung in Ppl -/-mice may have caused the decrease in STAT3 activation. However, Pedroza et al showed that C-188-9, a STAT3 inhibitor, decreased lung fibrosis through a decrease of epithelial injury and fibroblast-to-myofibroblast differentiation (18). Therefore, it would be interesting to see if PPL expression is altered in bleomycin-challenged mice during STAT3 inhibition in order to confirm the hierarchy of this pathway.…”