STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation
STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation
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DOI：
10.1096/fj.15-273953
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发表时间：
2016-01-01
期刊：
影响因子：
4.8
通讯作者：
Agarwal, Sandeep K.
中科院分区：
文献类型：
--
作者：
Pedroza, Mesias;Le, Thuy T.;Agarwal, Sandeep K.
肺纤维化是间质性肺疾病的标志。肺泡上皮细胞(AEC)损伤是促纤维化微环境形成的关键步骤。成纤维细胞和肌成纤维细胞随后积累和沉积过多的细胞外基质。除了转化生长因子-β，通过STAT-3传递信号的IL-6细胞因子家族也可能导致肺纤维化。在目前的手稿中，对STAT-3抑制在多大程度上减少肺纤维化进行了研究。特发性肺纤维化和博莱霉素(BLM)诱导的小鼠肺纤维化患者的肺活检组织中磷酸化STAT-3水平升高。通过动脉血氧饱和度(对照组，84.4+/-1.3%；C-188-9，94.4+/-0.8%)、组织学(Ashcroft评分：未经治疗，5.4+/-0.25；C-188-9，3.3+/-0.14)和减弱的纤维化标志物，如α-平滑肌肌动蛋白减少，胶原沉积减少，小分子STAT-3抑制剂C-188-9减少了BLM模型中的肺纤维化。此外，C-188-9还可降低缺氧诱导因子-1α(HIF-1α)和纤溶酶原激活物抑制物-1(PAI-1)等上皮损伤标志物的表达。体外研究表明，抑制STAT-3可降低IL-6和转化生长因子β诱导的血管内皮细胞多种基因的表达，包括HIF-1α和PAI-1。此外，C-188-9减少了成纤维细胞向肌成纤维细胞的分化。最后，肺成纤维细胞的转化生长因子-β刺激导致Smad2/Smad3依赖的STAT-3的磷酸化。这些发现表明STAT-3参与了肺纤维化的发展，并提示STAT-3可能是肺纤维化的治疗靶点。
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-1 alpha (HIF-1 alpha) 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-1 alpha 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.