布鲁顿酪氨酸激酶抑制剂可抑制病理性视网膜血管生成。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-10-07 DOI:10.1111/bph.17344
Siyue Chen, Yuming Liu, Yutian Zhang, Xu Guo, Tinghui Bai, Kai He, Yanfang Zhu, Yi Lei, Mei Du, Xiaohong Wang, Qiang Liu, Hua Yan
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引用次数: 0

摘要

背景和目的:病理性视网膜血管生成是威胁视力的眼部疾病的典型表现。许多患者对抗血管内皮生长因子(VEGF)药物反应不佳或产生抗药性。布鲁顿酪氨酸激酶(BTK)控制着免疫细胞的增殖和功能。因此,我们研究了抑制 BTK 对视网膜血管生成的抗炎和抗血管生成作用:实验方法:通过全装视网膜免疫荧光评估氧诱导视网膜病变 C57/BL6J 小鼠视网膜新生血管和血管渗漏的情况。用 PLX5622 清除小胶质细胞,用 Rag1 基因敲除小鼠测试淋巴细胞对 BTK 抑制作用的贡献。使用 qRT-PCR 和免疫荧光检测视网膜小胶质细胞/巨噬细胞的细胞因子、活化标志物、炎症和免疫调节活性。主要结果:BTK抑制抑制了小胶质细胞和人视网膜微血管内皮细胞(HRMECs)共培养的病理过程:主要结果:BTK抑制抑制了病理性血管生成和血管渗漏,并显著减轻了视网膜炎症,小胶质细胞/巨噬细胞参与了炎症,但淋巴细胞没有参与。BTK 抑制增加了抗炎因子,减少了 NLRP3 炎性体激活产生的促炎细胞因子。BTK 抑制剂抑制了小胶质细胞/巨噬细胞的炎症活性,并与抗血管内皮生长因子协同作用,不会对视网膜产生毒性。此外,与 BTK 抑制剂孵育的小胶质细胞上清液减少了 HRMECs 的增殖、管形成和发芽:BTK 抑制剂通过调节小胶质细胞和巨噬细胞的炎症活性抑制了视网膜新生血管和血管渗漏。我们的研究表明,抑制 BTK 是缓解病理性视网膜血管生成的一种新颖而有前景的方法。
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Bruton's tyrosine kinase inhibition suppresses pathological retinal angiogenesis.

Background and purpose: Pathological retinal angiogenesis is a typical manifestation of vision-threatening ocular diseases. Many patients exhibit poor response or resistance to anti-vascular endothelial growth factor (VEGF) agents. Bruton's tyrosine kinase (BTK) controls the proliferation and function of immune cells. Therefore, we examined the anti-inflammatory and anti-angiogenic effects of BTK inhibition on retinal angiogenesis.

Experimental approach: Retinal neovascularisation and vascular leakage in oxygen-induced retinopathy in C57/BL6J mice were assessed by whole-mount retinal immunofluorescence. PLX5622 was used to deplete microglia and Rag1-knockout mice were used to test the contribution of lymphocytes to the effects of BTK inhibition. The cytokines, activation markers, inflammatory and immune-regulatory activities of retinal microglia/macrophages were detected using qRT-PCR and immunofluorescence. NLRP3 was detected by western blotting, and the effects of BTK inhibition on the co-culture of microglia and human retinal microvascular endothelial cells (HRMECs) were examined.

Key results: BTK inhibition suppressed pathological angiogenesis and vascular leakage, and significantly reduced retinal inflammation, which involved microglia/macrophages but not lymphocytes. BTK inhibition increased anti-inflammatory factors and reduced pro-inflammatory cytokines that resulted from NLRP3 inflammasome activation. BTK inhibition suppressed the inflammatory activity of microglia/macrophages, and acted synergistically with anti-VEGF without retinal toxicity. Moreover, the supernatant of microglia incubated with BTK-inhibitor reduced the proliferation, tube formation and sprouting of HRMECs.

Conclusion and implications: BTK inhibition suppressed retinal neovascularisation and vascular leakage by modulating the inflammatory activity of microglia and macrophages. Our study suggests BTK inhibition as a novel and promising approach for alleviating pathological retinal angiogenesis.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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