Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.
Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.
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DOI：
10.7150/thno.72269
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Ye, Hong
中科院分区：
文献类型：
--
作者：
Wang, Meng;Liu, An Dong;Niu, Qian;Feng, Xiao;Zheng, Yuan-Yi;Chen, Shuai-Jun;Xu, Hui;Li, Qian;Hou, Guo-Qing;Bi, Xiao-Yang;Lu, Yu-Zhi;Cheng, Pei-Pei;Liang, Li-Mei;Jiang, Ye-Han;Zhao, Li-Qin;Liu, Fei;Song, Lin-Jie;Zhou, Li-Ling;Xiao, Ling-Yan;Chen, Feng;Li, Shawn Shun-Cheng;Ma, Wan-Li;Cao, Xuan;Ye, Hong
背景：特发性肺纤维化（IPF）是一种进行性、不可逆的纤维化疾病，死亡率高。目前，吡非尼酮和尼达尼布是美国食品和药物管理局（FDA）批准的唯一治疗IPF的药物，但它们的疗效有限。多种磷酸酪氨酸（pY）介导的信号通路的激活是IPF病理机制的基础。Src同源-2 （SH2）超结合体含有天然SH2结构域的三个氨基酸（AAs）突变，已被证明能够阻断磷酸酪氨酸（pY）途径。因此，我们旨在将SH2超粘结剂引入IPF的治疗中。方法：分析IPF患者数据库，检测IPF患者肺组织中pY水平。在IPF患者和博来霉素（BLM）处理小鼠的原代肺成纤维细胞中，研究了pY对细胞增殖、迁移和分化的影响，并检测了SH2超结合物的抗纤维化作用。在体内，我们在多个BLM小鼠模型中进一步验证了SH2超结合物的安全性和有效性。我们还比较了SH2超结合剂和尼达尼布的体内抗纤维化作用和副作用。结果：数据显示，与pY水平直接相关的细胞因子和生长因子通路在IPF中显著富集。高水平的pY可诱导肺成纤维细胞的异常增殖、迁移和分化。SH2超结合物阻断pY介导的信号通路，通过靶向成纤维细胞高pY水平抑制肺纤维化。与尼达尼布相比，SH2超结合剂在体内具有更好的治疗效果和更小的副作用。结论：SH2超结合剂在体外和体内均具有明显的抗纤维化作用，有望成为一种治疗IPF的有效方法。
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.
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影响因子：
82.9
作者：
Liang J;Zhang Y;Xie T;Liu N;Chen H;Geng Y;Kurkciyan A;Mena JM;Stripp BR;Jiang D;Noble PW
通讯作者：
Noble PW
影响因子：
37.3
作者：
Du Z;Lovly CM
通讯作者：
Lovly CM
影响因子：
7.3
作者：
Belov AA;Mohammadi M
通讯作者：
Mohammadi M
影响因子：
5.8
作者：
Hostettler KE;Zhong J;Papakonstantinou E;Karakiulakis G;Tamm M;Seidel P;Sun Q;Mandal J;Lardinois D;Lambers C;Roth M
通讯作者：
Roth M
影响因子：
10.1
作者：
Kramer, Frederike;Dernedde, Jens;Kappert, Kai
通讯作者：
Kappert, Kai