Rheumatology Division, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Transl Res. 2021 May;231:139-158. doi: 10.1016/j.trsl.2021.01.001. Epub 2021 Jan 7.
Systemic sclerosis (SSc) is an idiopathic autoimmune disease with a heterogeneous clinical phenotype ranging from limited cutaneous involvement to rapidly progressive diffuse SSc. The most severe SSc clinical and pathologic manifestations result from an uncontrolled fibrotic process involving the skin and various internal organs. The molecular mechanisms responsible for the initiation and progression of the SSc fibrotic process have not been fully elucidated. Recently it has been suggested that tyrosine protein kinases play a role. The implicated kinases include receptor-activated tyrosine kinases and nonreceptor tyrosine kinases. The receptor kinases are activated following specific binding of growth factors (platelet-derived growth factor, fibroblast growth factor, or vascular endothelial growth factor). Other receptor kinases are the discoidin domain receptors activated by binding of various collagens, the ephrin receptors that are activated by ephrins and the angiopoetin-Tie-2s receptors. The nonreceptor tyrosine kinases c-Abl, Src, Janus, and STATs have also been shown to participate in SSc-associated tissue fibrosis. Currently, there are no effective disease-modifying therapies for SSc-associated tissue fibrosis. Therefore, extensive investigation has been conducted to examine whether tyrosine kinase inhibitors (TKIs) may exert antifibrotic effects. Here, we review the role of receptor and nonreceptor tyrosine kinases in the pathogenesis of the frequently progressive cutaneous and systemic fibrotic alterations in SSc, and the potential of TKIs as SSc disease-modifying antifibrotic therapeutic agents.
系统性硬化症（SSc）是一种特发性自身免疫性疾病，具有从局限性皮肤受累到快速进展性弥漫性 SSc 不等的异质性临床表型。SSc 最严重的临床和病理表现是由涉及皮肤和各种内脏器官的失控纤维化过程引起的。导致 SSc 纤维化过程发生和进展的分子机制尚未完全阐明。最近有人提出，酪氨酸蛋白激酶在其中发挥作用。涉及的激酶包括受体激活的酪氨酸激酶和非受体酪氨酸激酶。受体激酶在特定生长因子（血小板衍生生长因子、成纤维细胞生长因子或血管内皮生长因子）结合后被激活。其他受体激酶是由各种胶原结合激活的盘状结构域受体，由 Ephrins 激活的 Ephrin 受体以及血管生成素-Tie-2s 受体。非受体酪氨酸激酶 c-Abl、Src、Janus 和 STATs 也已被证明参与 SSc 相关组织纤维化。目前，尚无有效的治疗 SSc 相关组织纤维化的疾病修饰疗法。因此，已经进行了广泛的研究，以检查酪氨酸激酶抑制剂（TKIs）是否可能发挥抗纤维化作用。在这里，我们回顾了受体和非受体酪氨酸激酶在 SSc 中常见的进行性皮肤和系统性纤维化改变发病机制中的作用，以及 TKIs 作为 SSc 疾病修饰性抗纤维化治疗药物的潜力。
