Wang Wenxia, Bhattacharyya Swati, Marangoni Roberta Goncalves, Carns Mary, Dennis-Aren Kathleen, Yeldandi Anjana, Wei Jun, Varga John
Northwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Surgical Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
J Scleroderma Relat Disord. 2020 Feb;5(1):40-50. doi: 10.1177/2397198319865367. Epub 2019 Aug 7.
Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized.
The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration-approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models.
Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice.
These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.
纤维化导致系统性硬化症患者皮肤、肺部及其他器官功能衰竭；是发病率和死亡率的重要原因；且缺乏有效治疗方法。肌成纤维细胞活化是器官纤维化的基础，但驱动该过程持续存在的关键细胞外信号仍未完全明确。
评估系统性硬化症患者皮肤和肺活检中与纤维化相关的IL6/JAK/STAT轴的活化情况，以及美国食品药品监督管理局批准的JAK/STAT抑制剂托法替布对动物模型皮肤和肺纤维化的影响。
生物信息学分析表明，在四个独立队列中，系统性硬化症患者的活检样本中IL6/JAK/STAT3和托法替布基因特征异常。系统性硬化症患者皮肤和肺活检中的JAK和STAT3磷酸化证实了这一结果。此外，用选择性JAK抑制剂托法替布治疗小鼠不仅可预防博来霉素诱导的皮肤和肺纤维化，还可减轻TSK1/+小鼠的皮肤纤维化。
这些发现表明JAK/STAT通路与系统性硬化症皮肤和肺纤维化有关，并确定托法替布为治疗系统性硬化症和其他纤维化疾病的潜在抗纤维化药物。
