Targeting USP11 may alleviate radiation-induced pulmonary fibrosis by regulating endothelium tight junction
Targeting USP11 may alleviate radiation-induced pulmonary fibrosis by regulating endothelium tight junction
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靶向 USP11 可能通过调节内皮紧密连接减轻辐射诱导的肺纤维化
DOI：
10.1080/09553002.2022.1998711
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发表时间：
2021-10
影响因子：
2.6
通讯作者：
Yang Jiao
中科院分区：
文献类型：
--
作者：
Yiting Tang;Qian Yuan;Congzhao Zhao;Ying Xu;Qi Zhang;Lili Wang;Zhiqiang Sun;Jianping Cao;Judong Luo;Yang Jiao
摘要目的放射性肺纤维化（RIPF）是胸部恶性肿瘤放疗后的主要副作用。然而，罕见的抗RIPF治疗剂显示出治疗这种疾病的明确效果。泛素特异性肽酶11（USP 11）可促进转化生长因子β（TGFβ）信号转导，在RIPF的形成中起重要作用。在此，我们探讨了USP 11在RIPF中的作用。材料与方法本研究以USP 11基因敲除小鼠（Usp 11-/-）为实验动物，探讨USP 11对RIPF的影响。X线照射30戈伊后取肺组织。采用免疫组化和Western Blot法分别检测USP 11、TGF-β1和α-SMA的表达。用荧光法检测γ-H2 AX灶和TUNEL阳性细胞的DNA损伤和凋亡情况。采用高通量蛋白质组学技术进一步探讨其作用机制。采用transwell共培养法研究了体外照射HMEC-1细胞诱导HELF细胞的旁观者效应。结果在体内和体外实验中，我们发现辐射激活了USP 11。我们的研究结果表明，USP 11缺陷可有效降低血清TGF-β1水平，抑制α-SMA表达，减轻肺纤维化。此外，在从Usp 11-/-小鼠肺分离的原代细胞中，在照射后鉴定出较少的γ-H2 AX灶和减少的凋亡细胞。高通量蛋白质组学分析结果显示，照射后Usp 11-/-小鼠肺组织中有22个蛋白质表达上调，158个蛋白质表达下调。此外，基因集富集分析（GSEA）显示，USP 11缺陷影响紧密连接信号通路。结论USP 11缺陷可增强内皮细胞紧密连接，抑制TGF-β1表达，从而抑制成纤维细胞纤维化。本研究初步表明USP 11基因敲除可通过增强内皮屏障功能减轻RIPF。
Abstract Purpose Radiation-induced pulmonary fibrosis (RIPF) is a major side effect after radiotherapy for thoracic malignancies. However, rare anti-RIPF therapeutics show definitive effects for treating this disease. Ubiquitin-specific peptidase 11 (USP11) has been reported to promote transforming growth factor β (TGFβ) signaling which plays an essential role underlying RIPF. Herein, we explored the role of USP11 on RIPF. Materials and methods In the present study, USP11-knockout (Usp11-/- ) mice were used to explore the effects of USP11 on RIPF. The lung tissue was obtained after receiving 30 Gy X-ray irradiation. The expression of USP11, TGF-β1, and a-SMA was determined by immunohistochemical and Western Blot, respectively. γ-H2AX foci and TUNEL positive cells were detected by fluorescent technique to assess DNA damage and apoptosis. High-throughput proteomic analysis was applied to further explore the related mechanisms. The transwell co-culture method was used to investigate bystander effects in HELF cells induced by irradiated HMEC-1 cells in vitro. Results Here we found that radiation activated USP11 in vivo and in vitro. Our results showed that USP11 deficiency effectively decreased serum TGF-β1 level, suppressed α-SMA expression, and mitigated pulmonary fibrosis. In addition, fewer γ-H2AX foci and decreased apoptotic cells were identified after irradiation in the primary cells isolated from the lungs of Usp11-/- mice. High-throughput proteomics analysis results showed that 22-upregulated and 158-downregulated proteins were identified in the lung tissues of Usp11-/- mice after irradiation. Furthermore, gene set enrichment analysis (GSEA) revealed that USP11 deficiency affects the tight junction signaling pathway. Conclusions We verified that USP11 deficiency remarkably reinforced tight junction in the endothelial cells and alleviated TGF-β1 to inhibit fibrosis of fibroblast cells. The present study preliminarily showed that USP11-knockout mitigated RIPF via reinforcement endothelial barrier function.
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影响因子：
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作者：
Yang X;Xu X;Zhu J;Zhang S;Wu Y;Wu Y;Zhao K;Xing C;Cao J;Zhu H;Li M;Ye Z;Peng W
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DOI：
10.1891/9780826121646.0002
发表时间：
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期刊：
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影响因子：
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DOI：
10.1016/s0360-3016(01)01593-0
发表时间：
2001-07-15
影响因子：
7
作者：
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通讯作者：
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