Evaluation of the TGF-ß induced activation of JAK2 / STAT3 signaling as a key-pathway for fibroblast activation in fibrotic diseases

纤维化疾病给现代社会造成了重大的社会经济负担，在发达国家死亡人数中占比高达45%。所有纤维化疾病的共同组织病理学特征是细胞外基质的过度积累，这是由持续激活的成纤维细胞释放的。导致成纤维细胞病理活化的分子机制尚不完全清楚，因此，治疗纤维化疾病的有效靶向治疗尚不可用。我们首次证明了转化生长因子- β (tgf - β)激活成纤维细胞中的JAK2 / STAT3信号，并且成纤维细胞中JAK2 / STAT3信号的激活是纤维化疾病的共同特征。我们还发现，tgf - β的促纤维化作用需要JAK2 / STAT3的激活，因为在体外，JAK2的药理学或遗传失活抑制tgf - β诱导的成纤维细胞激活，并在体内的小鼠系统性纤维化模型中阻止纤维化。我们现在的目标是进一步研究JAK2和STAT3作为抗纤维化治疗的潜在靶点。我们计划在实验性纤维化模型中使用小分子抑制剂和成纤维细胞特异性缺失STAT3的小鼠抑制STAT3信号。我们还计划表征TGF-ß激活JAK2 / STAT3信号的分子机制。此外，我们将分析JAK2 / STAT3如何激活肌成纤维细胞分化并刺激胶原蛋白的释放。最后，我们将把我们的研究结果从SSc的临床前模型转移到其他具有JAK2 / STAT3信号增强的纤维化疾病，并分析JAK2-和STAT3抑制在特发性肺纤维化（IPF）、硬皮病移植物抗宿主病（cGvHD）、肾纤维化和非酒精性肝纤维化的小鼠模型中的抗纤维化作用。我们相信我们的研究可能具有直接的转化意义，因为第一个JAK抑制剂已经被批准用于类风湿性关节炎和骨髓增生性疾病的临床应用，因此可以用于纤维化疾病的临床试验。此外，其他JAK2-和STAT3抑制剂目前正在临床开发中。

Fibrotic diseases impose a major socioeconomic burden on modern societies and account for up to 45% of deaths in the developed world. The common histopathological feature of all fibrotic disorders is an excessive accumulation of extracellular matrix, which is released by persistently activated fibroblasts. The molecular mechanisms that lead to the pathologic activation of fibroblasts are incompletely understood and consequently, effective targeted therapies are not yet available for the treatment of fibrotic diseases. We demonstrated for the first time that transforming growth factor-beta (TGF-beta) activates JAK2 / STAT3 signaling in fibroblasts and that activation of JAK2 / STAT3 signaling in fibroblasts is a common feature of fibrotic diseases. We also showed that activation of JAK2 / STAT3 is required for the pro-fibrotic effects of TGF-beta, because pharmacologic or genetic inactivation of JAK2 inhibits TGF-beta induced fibroblasts activation in vitro and prevents fibrosis in murine models of systemic fibrosis in vivo. We now aim to further investigate JAK2 and STAT3 as potential targets for anti-fibrotic therapies. We plan to inhibit STAT3 signaling in experimental models of fibrosis using small molecule inhibitors and mice with fibroblast-specific deletion of STAT3. We also plan to characterize the molecular mechanisms, by which TGF-ß activates JAK2 / STAT3 signaling. Moreover, we will analyze how JAK2 / STAT3 activate myofibroblast differentiation and stimulate the release of collagen. Finally, we will transfer our findings from preclinical models of SSc to other fibrotic diseases with enhanced JAK2 / STAT3 signaling and analyze the anti-fibrotic effects of JAK2- and STAT3 inhibition in murine models of idiopathic pulmonary fibrosis (IPF), sclerodermatous graft-versus-host disease (cGvHD), renal fibrosis and non-alcoholic liver fibrosis. We believe that our study may have direct translational implications, because first JAK inhibitors have already been approved for clinical use in rheumatoid arthritis and myeloproliferative diseases and would thus be available for clinical trials in fibrotic diseases. Moreover, additional JAK2- and STAT3 inhibitors are currently in clinical development.