用可溶性死亡受体 5 融合蛋白阻断 TRAIL-DR5 信号通路可减轻辐射损伤,Frontiers in Pharmacology

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用可溶性死亡受体 5 融合蛋白阻断 TRAIL-DR5 信号通路可减轻辐射损伤
Frontiers in Pharmacology ( IF 4.4 ) Pub Date : 2023-05-18 , DOI: 10.3389/fphar.2023.1171293
Danyang Zhao _{1,

2} , Lei Yang ₂ , Peng Han ₂ , Haihui Zhang ₂ , Fanjun Wang ₂ , Zhiyun Meng ₂ , Hui Gan ₂ , Zhuona Wu ₂ , Wenzhong Sun ₂ , Chuan Chen ₁ , Guifang Dou ₂ , Ruolan Gu ₂

Affiliation

核技术应用日益广泛、急性辐射综合征（ARS）病死率高、机制复杂，使ARS成为亟待关注的全球性难题。在这里，我们报道了死亡受体 5 (DR5) 及其配体肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 在小鼠接受 6 Gy γ 射线单次辐射后均显着上调。并通过静脉内给予DR5的竞争性拮抗剂可溶性DR5融合蛋白（sDR5-Fc），显着抑制脾脏和胸腺等辐射敏感组织的过度细胞凋亡，减轻脾脏和胸腺的辐射损伤，而细胞凋亡抑制蛋白如 Bcl-2 的表达也显着上调。sDR5-Fc给药改善了受辐射影响的生化指标，如血清ALP、AST、ALT、TBIL、K和Cl水平。sDR5-Fc 还可以调节免疫细胞的数量并减少血细胞死亡。为了体外流式细胞仪研究发现sDR5-Fc能有效抑制人小肠黏膜上皮细胞和IEC-6细胞的凋亡。最后，生存研究表明，在 9 Gy γ 射线单次全身辐射后给予 sDR5-Fc 的小鼠有效增加了 30 天的存活率，并且呈显着的剂量依赖性。总体而言，研究结果表明，DR5/TRAIL 介导的细胞凋亡通路在 ARS 小鼠的损伤中发挥了重要作用，DR5 可能是 ARS 治疗的潜在靶点。而 DR5 凋亡拮抗剂 sDR5 融合蛋白可能是一种有前途的抗 ARS 候选药物，值得进一步研究。

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Blocking TRAIL-DR5 signaling pathway with soluble death receptor 5 fusion protein mitigates radiation-induced injury

The increasing application of nuclear technology, the high fatality of acute radiation syndrome (ARS) and its complex mechanism make ARS a global difficulty that requires urgent attention. Here we reported that the death receptor 5 (DR5), as well as its ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were both significantly upregulated after irradiation in mice with 6 Gy γ-ray single radiation. And by intravenously administrated with soluble DR5 fusion protein (sDR5-Fc), the competitive antagonist of DR5, the excessive apoptosis in the radiation-sensitive tissues such as spleen and thymus were significantly inhibited and the radiation-induced damage of spleen and thymus were mitigated, while the expression of apoptosis-inhibiting proteins such as Bcl-2 was also significantly upregulated. The biochemical indicators such as serum ALP, AST, ALT, TBIL, K, and Cl levels that affected by radiation, were improved by sDR5-Fc administration. sDR5-Fc can also regulate the number of immune cells and reduce blood cell death. For in vitro studies, it had been found that sDR5-Fc effectively inhibited apoptosis of human small intestinal mucosal epithelial cells and IEC-6 cells using flow cytometry. Finally, survival studies showed that mice administrated with sDR5-Fc after 9 Gy γ-ray single whole body radiation effectively increased the 30-day survival and was in a significant dose-dependent manner. Overall, the findings revealed that DR5/TRAIL-mediated apoptosis pathway had played important roles in the injury of ARS mice, and DR5 probably be a potential target for ARS therapeutics. And the DR5 apoptosis antagonist, sDR5 fusion protein, probably is a promising anti-ARS drug candidate which deserves further investigation.

更新日期：2023-05-18

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