胍丁胺通过芳烃受体-信号转导和转录激活因子3-白细胞介素10途径改善脓毒症相关的肠道损伤。

Agmatine ameliorates sepsis-related intestinal injury via the AhR-STAT3-IL-10 pathway.

作者信息

Pan Junhua, Gan Lianfang, Chen Yaying, Zhong Lifan, Deng Huiming, Huang Ling, Liang Huaping

机构信息

College of Pharmacy, Hainan Medical University, Haikou, China; School of Hainan Provincial Drug Safety Evaluation Research Center, Hainan Medical University, Haikou, China; Guangdong Zhaoqing Aviation Vocational College, Zhaoqing, China.

School of Hainan Provincial Drug Safety Evaluation Research Center, Hainan Medical University, Haikou, China.

出版信息

Mol Immunol. 2025 Aug;184:76-88. doi: 10.1016/j.molimm.2025.06.004. Epub 2025 Jun 13.

DOI:10.1016/j.molimm.2025.06.004

PMID:40516501

Abstract

BACKGROUND

Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism.

METHODS

We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-α induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot.

RESULTS

The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1β, IL-6, and TNF-α, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway.

DISCUSSION AND CONCLUSION

AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3-IL-10 pathway, thereby offering theoretical basis for clinical treatment of sepsis.

摘要

背景

脓毒症相关的肠道损伤在全身炎症反应诱导的多器官功能障碍中至关重要。胍丁胺（AGM）具有抗炎、抗氧化和免疫调节特性。然而，尚未发现有关于AGM减轻脓毒症相关肠道损伤的报道。因此，本研究旨在探讨AGM对脓毒症相关肠道损伤的保护作用及其潜在机制。

方法

我们首先通过脂多糖（LPS）或盲肠结扎穿孔（CLP）建立脓毒症模型，然后使用苏木精-伊红（H&E）染色、透射电子显微镜（TEM）和TUNEL检测AGM处理后大鼠肠道的病理变化。采用酶联免疫吸附测定（ELISA）检测回肠组织中炎症因子的表达水平和血清中感染相关的生化指标。体外建立肿瘤坏死因子-α（TNF-α）诱导的Caco-2细胞炎症模型，AGM处理后通过细胞计数试剂盒-8（CCK8）和5-乙炔基-2'-脱氧尿苷（EdU）检测细胞活性和增殖能力。建立芳烃受体（AhR）高表达或低表达的Caco-2细胞炎症模型，采用分子对接、免疫共沉淀（Co-IP）和蛋白质免疫印迹法（Western Blot）研究AGM是否通过AhR/信号转导和转录激活因子3（STAT3）/白细胞介素-10（IL-10）途径发挥抗炎作用。

结果

组织病理学染色表明，AGM显著减轻肠道损伤以及炎症因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和TNF-α的含量，改善全身感染情况及脓毒症小鼠的存活率，并恢复CLP大鼠的肠道屏障功能。在体外，AGM提高了Caco-2细胞炎症模型的细胞活力和增殖能力。AGM通过激活AhR、降低缺氧诱导因子-1（HIF-1）蛋白表达并激活STAT3/IL-10信号通路来抑制炎症因子表达。