Department of Respiratory and Critical Care Medicine, Henan Provincial People's Hospital (People's Hospital of Zhengzhou University), Zhengzhou, China.
Pulmonary and Critical Care Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China.
Cell Mol Life Sci. 2024 Oct 25;81(1):438. doi: 10.1007/s00018-024-05474-y.
In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage.
在脓毒症患者中，中性粒细胞凋亡往往与脓毒症的严重程度呈反比，但具体机制尚不清楚。本研究旨在通过联合分析肠道微生物群和短链脂肪酸（SCFAs）代谢来探讨脂肪酸结合蛋白 4（FABP4）调节中性粒细胞凋亡的机制。首先，从脓毒症诱导的急性呼吸窘迫综合征（ARDS）患者的支气管肺泡灌洗液（BALF）中纯化并分离出中性粒细胞，应用 RNA 进行测序。然后，采用盲肠结扎穿孔（CLP）方法诱导小鼠脓毒症模型。在干预差异 SCFAs 醋酸钠后，进一步分析中性粒细胞凋亡和 FABP4 表达。然后，用 FABP4 抑制剂 BMS309403 处理中性粒细胞。我们发现 CLP 组的肺损伤评分、肺组织湿/干比、肺血管通透性以及支气管肺泡灌洗液和肺组织中的炎症因子 IL-1β、TNF-α、IL-6、IFN-γ 和 CCL3 水平均升高。此外，ARDS 患者和小鼠中性粒细胞中的 FABP4 水平较低。同时，观察到 CLP 诱导的肠道微生物群失调和 SCFAs 水平变化。进一步验证表明，醋酸通过 FFAR2 降低中性粒细胞凋亡和 FABP4 表达。此外，FABP4 通过内质网（ER）应激影响中性粒细胞凋亡，中性粒细胞耗竭减轻了 BMS309403 对 ARDS 发展的促进作用。此外，中性粒细胞中的 FABP4 通过炎症因子调节 RLE-6TN 的损伤。总之，受肠道微生物群衍生的 SCFAs 影响的 FABP4 通过 ER 应激延迟中性粒细胞凋亡，导致介导肺上皮细胞损伤的炎症因子增加。
