Xie Cancan, Wang Ting, Liu Anmin, Huang Bing, Zeng Weizhong, Li Zhengrong, Peng Suna, Wu Shuanghua
Department of Critical Care Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, China.
Department of Rehabilitation Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, China.
Cell Biochem Biophys. 2025 Jun;83(2):1785-1798. doi: 10.1007/s12013-024-01588-z. Epub 2024 Oct 14.
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.
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).
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.
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.
脓毒症诱导的急性肺损伤（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。脓毒症诱导ALI的潜在机制仍知之甚少。在此，我们确定了沉默调节蛋白4（SIRT4）对脓毒症诱导ALI的影响。
建立脂多糖（LPS）诱导的损伤细胞模型和盲肠结扎穿孔（CLP）动物模型。使用过表达载体和慢病毒转染上调SIRT4表达。评估肺细胞凋亡、炎症及相关因子水平。检测PI3K/AKT/mTOR和JAK2/STAT3信号通路的变化，并使用LY294002（PI3K抑制剂）、740 Y-P（PI3K激动剂）、AG490（JAK2抑制剂）和香豆霉素A1（JAK2激动剂）研究其潜在作用。
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过表达增强细胞活力、抵抗细胞凋亡、恢复凋亡相关蛋白（HMB1、裂解的CASP3、BAX和BCL）的表达，并减少促炎细胞因子（IL-6、IL-1β和TNF-α）的分泌。在CLP大鼠中，Sirt4过表达延长生存时间、减轻肺组织病理学损伤、减少肺水肿、减轻肺部感染、降低肺细胞凋亡，并降低血清炎症细胞因子水平。此外，Sirt4过表达阻断JAK2/STAT3/AKT/mTOR磷酸化。740 Y-P和香豆霉素A1逆转了Sirt4过表达对LPS处理的A549细胞的保护作用，导致细胞活力降低和细胞凋亡增加。LY294002和AG490增强了Sirt4过表达对LPS处理的A549细胞的保护作用。
SIRT4通过抑制JAK2/STAT3/PI3K/AKT/mTOR信号减轻脓毒症诱导的ALI。上调SIRT4表达可能是脓毒症肺损伤治疗的一种创新方法。
