Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43300, Malaysia.
Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43300, Malaysia.
Eur J Pharmacol. 2021 Nov 15;911:174510. doi: 10.1016/j.ejphar.2021.174510. Epub 2021 Sep 21.
Transforming growth factor-beta (TGF-β) plays multiple homeostatic roles in the regulation of inflammation, proliferation, differentiation and would healing of various tissues. Many studies have demonstrated that TGF-β stimulates activation and proliferation of fibroblasts, which result in extracellular matrix deposition. Its increased expression can result in many fibrotic diseases, and the level of expression is often correlated with disease severity. On this basis, inhibition of TGF-β and its activity has great therapeutic potential for the treatment of various fibrotic diseases such as pulmonary fibrosis, renal fibrosis, systemic sclerosis and etc. By understanding the molecular mechanism of TGF-β signaling and activity, researchers were able to develop different strategies in order to modulate the activity of TGF-β. Antisense oligonucleotide was developed to target the mRNA of TGF-β to inhibit its expression. There are also neutralizing monoclonal antibodies that can target the TGF-β ligands or αβ integrin to prevent binding to receptor or activation of latent TGF-β respectively. Soluble TGF-β receptors act as ligand traps that competitively bind to the TGF-β ligands. Many small molecule inhibitors have been developed to inhibit the TGF-β receptor at its cytoplasmic domain and also intracellular signaling molecules. Peptide aptamer technology has been used to target downstream TGF-β signaling. Here, we summarize the underlying mechanism of TGF-β-induced fibrosis and also review various strategies of inhibiting TGF-β in both preclinical and clinical studies.
转化生长因子-β（TGF-β）在调节炎症、增殖、分化和组织愈合方面发挥着多种稳态作用。许多研究表明，TGF-β刺激成纤维细胞的激活和增殖，导致细胞外基质的沉积。其表达增加可导致多种纤维化疾病，其表达水平常与疾病严重程度相关。在此基础上，抑制 TGF-β及其活性对治疗肺纤维化、肾纤维化、系统性硬化症等多种纤维化疾病具有巨大的治疗潜力。通过了解 TGF-β信号和活性的分子机制，研究人员能够制定不同的策略来调节 TGF-β的活性。反义寡核苷酸被开发用于靶向 TGF-β 的 mRNA 以抑制其表达。也有中和单克隆抗体可以靶向 TGF-β配体或αβ整合素，分别防止与受体结合或激活潜伏的 TGF-β。可溶性 TGF-β受体作为配体陷阱，竞争性地与 TGF-β配体结合。已经开发出许多小分子抑制剂来抑制 TGF-β受体的胞质结构域以及细胞内信号分子。肽适体技术已被用于靶向下游 TGF-β信号。在这里，我们总结了 TGF-β 诱导纤维化的潜在机制，并综述了在临床前和临床研究中抑制 TGF-β 的各种策略。
