Pyroptosis inhibition alleviates acute lung injury via E-twenty-six variant gene 5-mediated downregulation of gasdermin D

IF 1.9 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology Pub Date : 2024-09-11 DOI:10.1016/j.resp.2024.104346

Wenlong Zhang , Xinhua Wang , Chenhui Ma, Bao Liang, Lihong Ma, Yan Wang, Yuanjie Lin, Shuguang Han

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引用次数: 0

Abstract

Background

Acute lung injury (ALI) is a life-threatening condition characterized by excessive pulmonary inflammation, yet its precise pathophysiology remains elusive. Pyroptosis, a programmed cell death mechanism controlled by gasdermin D (GSDMD), has been linked to the etiology of ALI. This study investigated the regulatory functions of the transcription factor E-twenty-six variant gene 5 (ETV5) and GSDMD in ALI.

Methods

Lipopolysaccharide (LPS) was used to treat BEAS-2B cells (50 mmol/mL) and establish an LPS-induced mouse model of ALI (by intratracheal administration, 3 mg/kg). Protein-protein docking, immunofluorescence analysis, western blotting, real-time quantitative polymerase chain reaction, and dual-luciferase reporter gene assay were used to examine ETV5-mediated negative feedback regulation of GSDMD and its effects on pyroptosis and ALI.

Results

Our results showed that the physiological function of ETV5 was reduced by its downregulated expression, which impeded its nuclear translocation in ALI mice. Increased pyroptosis and enhanced production of inflammatory cytokines were associated with LPS-induced ALI. ETV5 overexpression in LPS-treated BEAS-2B cells decreased the expression of total and membrane-bound GSDMD, negatively regulated GSDMD, and prevented pyroptosis. The expression of inflammatory cytokines was subsequently reduced due to this inhibition, which, in turn, reduced ALI. Molecular docking analysis and dual-luciferase reporter gene assay results indicated a direct interaction between ETV5 and GSDMD, which inhibited GSDMD production.

Conclusion

Our results indicate that ETV5 inhibits pyroptosis, decreases the expression of inflammatory cytokines, and negatively regulates GSDMD expression to ameliorate ALI symptoms.

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通过 E-twenty-six 变异基因 5 介导的 gasdermin D 下调，抑制裂解酶可减轻急性肺损伤

背景急性肺损伤（ALI）是一种以过度肺部炎症为特征的危及生命的疾病，但其确切的病理生理学至今仍不清楚。由 gasdermin D（GSDMD）控制的一种程序性细胞死亡机制--嗜热细胞增多症（Pyroptosis）与急性肺损伤的病因有关。方法用脂多糖（LPS）处理 BEAS-2B 细胞（50 毫摩尔/毫升）并建立 LPS 诱导的 ALI 小鼠模型（气管内给药，3 毫克/千克）。结果我们的研究结果表明，ETV5 的生理功能因其表达下调而降低，这阻碍了其在 ALI 小鼠中的核转位。ETV5的表达下调阻碍了其在ALI小鼠体内的核转运，从而降低了其生理功能。在经 LPS 处理的 BEAS-2B 细胞中过表达 ETV5 可降低总 GSDMD 和膜结合 GSDMD 的表达，对 GSDMD 进行负调控，并防止细胞脓毒症。由于这种抑制作用，炎性细胞因子的表达随之减少，进而减少了 ALI。分子对接分析和双荧光素酶报告基因检测结果表明，ETV5 与 GSDMD 之间存在直接相互作用，从而抑制了 GSDMD 的产生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Respiratory Physiology & Neurobiology 医学-呼吸系统

CiteScore

4.80

自引率

8.70%

发文量

104

审稿时长

54 days

期刊介绍： Respiratory Physiology & Neurobiology (RESPNB) publishes original articles and invited reviews concerning physiology and pathophysiology of respiration in its broadest sense. Although a special focus is on topics in neurobiology, high quality papers in respiratory molecular and cellular biology are also welcome, as are high-quality papers in traditional areas, such as: -Mechanics of breathing- Gas exchange and acid-base balance- Respiration at rest and exercise- Respiration in unusual conditions, like high or low pressure or changes of temperature, low ambient oxygen- Embryonic and adult respiration- Comparative respiratory physiology. Papers on clinical aspects, original methods, as well as theoretical papers are also considered as long as they foster the understanding of respiratory physiology and pathophysiology.