Trichloroethylene (TCE), a widely distributed environmental chemical contaminant, is extensively dispersed throughout the environment. Individuals who are exposed to TCE may manifest occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Renal impairment typically manifests in the initial phase of OMDT and is intricately linked to the disease progression and patient outcomes. Although recombinant human tumor necrosis factor-α receptor II fusion protein (rh TNFR:Fc) has been employed in the clinical management of OMDT, there was no substantial improvement in renal function observed in patients following one week of treatment. This study primarily examined the mechanism of TNFα- and IFNγ-induced endothelial cells (ECs) PANoptosis in TCE-induced kidney injury and hypothesized that the synergistic effect of TNFα and IFNγ could be the key factor affecting the efficacy of rh TNFR:Fc therapy in OMDT patients. A TCE-sensitized mouse model was utilized in this study to investigate the effects of TNFα and IFNγ neutralizing antibodies on renal vascular endothelial cell PANoptosis. The gene of interferon regulatory factor 1 (IRF1) in human umbilical vein endothelial cells (HUVEC) was silenced by using small interfering RNA (siRNA), and the cells were then treated with TNFα and IFNγ recombinant protein to investigate the mechanism of TNFα combined with IFNγ-induced PANoptosis in HUVEC. The findings indicated that mice sensitized to TCE exhibited increased levels of PANoptosis-related markers in renal endothelial cells, and treatment with TNFα and IFNγ neutralizing antibodies resulted in a significant reduction in PANoptosis and improvement in renal function. experiments demonstrated that silencing IRF1 could reverse TNFα and IFNγ-induced PANoptosis in endothelial cells. These results suggest that the efficacy of rh TNFR:Fc may be influenced by TNFα and IFNγ-mediated PANoptosis in kidney vascular endothelial cells. The joint application of TNFα and IFNγ neutralizing antibody represented a solid alternative to existing therapeutics.

中文翻译：

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肾血管内皮细胞全凋亡的作用：对三氯乙烯诱导的肾损伤的影响


三氯乙烯（TCE）是一种广泛分布的环境化学污染物，广泛分布在整个环境中。接触 TCE 的个体可能会因三氯乙烯 (OMDT) 而出现职业性药物性皮炎。肾损伤通常出现在 OMDT 的初始阶段，并且与疾病进展和患者结果密切相关。尽管重组人肿瘤坏死因子-α受体II融合蛋白（rh TNFR:Fc）已用于OMDT的临床治疗，但治疗1周后，并未观察到患者肾功能的实质性改善。本研究主要探讨了 TCE 肾损伤中 TNFα 和 IFNγ 诱导内皮细胞（EC）全凋亡的机制，并推测 TNFα 和 IFNγ 的协同作用可能是影响 rh TNFR:Fc 治疗效果的关键因素。 OMDT 患者。本研究采用TCE致敏小鼠模型来研究TNFα和IFNγ中和抗体对肾血管内皮细胞全凋亡的影响。采用小干扰RNA（siRNA）沉默人脐静脉内皮细胞（HUVEC）干扰素调节因子1（IRF1）基因，然后用TNFα和IFNγ重组蛋白处理细胞，探讨TNFα联合IFNγ的作用机制。 HUVEC 中 IFNγ 诱导的全凋亡。研究结果表明，对 TCE 敏感的小鼠肾内皮细胞中 PANoptosis 相关标记物的水平升高，用 TNFα 和 IFNγ 中和抗体治疗可导致 PANoptosis 显着减少并改善肾功能。 实验表明，沉默 IRF1 可以逆转 TNFα 和 IFNγ 诱导的内皮细胞 PANoptosis。这些结果表明，rh TNFR:Fc 的功效可能受到肾血管内皮细胞中 TNFα 和 IFNγ 介导的 PANoptosis 的影响。 TNFα 和 IFNγ 中和抗体的联合应用代表了现有疗法的可靠替代方案。