Sirt4 Overexpression Modulates the JAK2/STAT3 and PI3K/AKT/mTOR Axes to Alleviate Sepsis-Induced Acute Lung Injury.

IF 1.8 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Biochemistry and Biophysics Pub Date : 2024-10-14 DOI:10.1007/s12013-024-01588-z

Cancan Xie, Ting Wang, Anmin Liu, Bing Huang, Weizhong Zeng, Zhengrong Li, Suna Peng, Shuanghua Wu

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Abstract

Background: Sepsis-induced acute lung injury (ALI) is a severe organ dysfunction characterized by lung inflammation and apoptosis. The mechanisms underlying sepsis-induced ALI remain poorly understood. Here, we determined the effects of sirtuin 4 (SIRT4) on sepsis-induced ALI.

Methods: Lipopolysaccharide (LPS)-induced injury cell and cecal ligation and puncture (CLP) animal models were established. Overexpression vectors and lentiviral transfections were used to upregulate SIRT4 expression. Lung cell apoptosis, inflammation, and the levels of associated factors were evaluated. Changes in the PI3K/AKT/mTOR and JAK2/STAT3 pathways were measured, and their potential involvement was examined using LY294002 (PI3K inhibitor), 740 Y-P (PI3K agonist), AG490 (JAK2 inhibitor), and coumermycin A1 (JAK2 agonist).

Results: Lower SIRT4 expression was observed in LPS-exposed A549 cells and CLP rats. In LPS-induced A549 cells, Sirt4 overexpression enhanced cell viability, resisted apoptosis, restored the expression of apoptosis-associated proteins (HMB1, cleaved CASP3, BAX, and BCL), and reduced the secretion of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). In CLP rats, Sirt4 overexpression prolonged survival time, alleviated lung histopathological damage, reduced pulmonary edema, mitigated lung infection, decreased lung apoptosis, and lowered serum levels of inflammatory cytokines. Furthermore, Sirt4 overexpression blocked JAK2/STAT3/AKT/mTOR phosphorylation. 740 Y-P and coumermycin A1 reversed the protective effects of Sirt4 overexpression in LPS-treated A549 cells, resulting in decreased cell viability and increased apoptosis. LY294002 and AG490 enhanced the protective effects of Sirt4 overexpression in LPS-treated A549 cells.

Conclusion: SIRT4 alleviates sepsis-induced ALI by inhibiting JAK2/STAT3/PI3K/AKT/mTOR signaling. Upregulating SIRT4 expression may serve as an innovative therapeutic approach for lung injury management in sepsis.

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Sirt4过表达调节JAK2/STAT3和PI3K/AKT/mTOR轴，缓解败血症诱发的急性肺损伤

背景：脓毒症诱发的急性肺损伤（ALI）是一种以肺部炎症和细胞凋亡为特征的严重器官功能障碍。脓毒症诱发 ALI 的机制仍不甚明了。在此，我们确定了sirtuin 4（SIRT4）对脓毒症诱导的ALI的影响：方法：建立了脂多糖（LPS）诱导的损伤细胞和盲肠结扎穿刺（CLP）动物模型。过表达载体和慢病毒转染用于上调 SIRT4 的表达。对肺细胞凋亡、炎症和相关因子的水平进行了评估。测量了 PI3K/AKT/mTOR 和 JAK2/STAT3 通路的变化，并使用 LY294002（PI3K 抑制剂）、740 Y-P（PI3K 激动剂）、AG490（JAK2 抑制剂）和 coumermycin A1（JAK2 激动剂）检测了它们的潜在参与：结果：在暴露于LPS的A549细胞和CLP大鼠中观察到较低的SIRT4表达。在 LPS 诱导的 A549 细胞中，Sirt4 的过表达增强了细胞活力，抑制了细胞凋亡，恢复了细胞凋亡相关蛋白（HMB1、裂解 CASP3、BAX 和 BCL）的表达，并减少了促炎细胞因子（IL-6、IL-1β 和 TNF-α）的分泌。在CLP大鼠中，Sirt4的过表达延长了存活时间，减轻了肺组织病理学损伤，减轻了肺水肿，缓解了肺部感染，减少了肺凋亡，并降低了血清中炎性细胞因子的水平。此外，Sirt4 的过表达还能阻止 JAK2/STAT3/AKT/mTOR 磷酸化。在经 LPS 处理的 A549 细胞中，740 Y-P 和库莫霉素 A1 逆转了 Sirt4 过表达的保护作用，导致细胞活力下降和凋亡增加。LY294002和AG490增强了Sirt4过表达对LPS处理的A549细胞的保护作用：结论：SIRT4 可通过抑制 JAK2/STAT3/PI3K/AKT/mTOR 信号转导缓解败血症诱导的 ALI。上调 SIRT4 的表达可作为治疗脓毒症肺损伤的一种创新方法。

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来源期刊

Cell Biochemistry and Biophysics 生物-生化与分子生物学

CiteScore

4.40

自引率

0.00%

发文量

审稿时长

7.5 months

期刊介绍： Cell Biochemistry and Biophysics (CBB) aims to publish papers on the nature of the biochemical and biophysical mechanisms underlying the structure, control and function of cellular systems The reports should be within the framework of modern biochemistry and chemistry, biophysics and cell physiology, physics and engineering, molecular and structural biology. The relationship between molecular structure and function under investigation is emphasized. Examples of subject areas that CBB publishes are: · biochemical and biophysical aspects of cell structure and function; · interactions of cells and their molecular/macromolecular constituents; · innovative developments in genetic and biomolecular engineering; · computer-based analysis of tissues, cells, cell networks, organelles, and molecular/macromolecular assemblies; · photometric, spectroscopic, microscopic, mechanical, and electrical methodologies/techniques in analytical cytology, cytometry and innovative instrument design For articles that focus on computational aspects, authors should be clear about which docking and molecular dynamics algorithms or software packages are being used as well as details on the system parameterization, simulations conditions etc. In addition, docking calculations (virtual screening, QSAR, etc.) should be validated either by experimental studies or one or more reliable theoretical cross-validation methods.