Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis.
Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis.
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DOI：
10.3904/kjim.2014.29.3.281
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Lee CG
中科院分区：
文献类型：
--
作者：
Lee CM;Park JW;Cho WK;Zhou Y;Han B;Yoon PO;Chae J;Elias JA;Lee CG
肺纤维化是一种致命的进行性疾病，目前尚无有效的治疗方法。转化生长因子（transforminggrowthfactor，TGF）-β1长期以来被认为是组织纤维化的中心介质，涉及包括皮肤、肝、肾和肺在内的多个器官。因此，TGF-β1及其信号通路已成为抗纤维化药物开发的有吸引力的治疗靶标。然而，TGF-β1在维持正常免疫和细胞稳态方面的基本生物学功能显著限制了TGF-β1导向的治疗方法的有效性。因此，靶向TGF-β1的下游介质或信号传导分子可能是选择性抑制TGF-β1刺激的纤维化组织反应同时保留TGF-β1的主要生理功能的替代方法。本实验室最近的研究表明，TGF-β1通过诱导表皮生长因子受体（EGFR）的配体双调蛋白（Amphiregulin）而与EGFR信号转导发生串扰，在肺纤维化的发生或进展中起关键作用。此外，壳三糖苷酶（chitotriosidase）是人类中的一种真正的几丁质酶，已被鉴定为具有TGF-β1信号传导的调节能力，作为硬皮病相关肺纤维化的新生物标志物和治疗靶点。这些新发现的TGF-β1效应功能调节剂显著增强了靶向肺纤维化的有效性和灵活性，其中TGF-β1起着重要作用。
Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-β1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-β1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-β1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-β1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-β1 could be an alternative approach that selectively inhibits TGF-β1-stimulated fibrotic tissue response while preserving major physiological function of TGF-β1. Recent studies from our laboratory revealed that TGF-β1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-β1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-β1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-β1 plays a significant role.
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