Xue Lexin, Xu Jingran, Gong Hui, Abudureheman Zulipikaer, ALimu Ayiguli, Chen Yun, Zheng Aifang, Gao Liang, Lu Xiuqi, Xie Chengxin, Li Li
Department of Respiratory and Critical Care Medicine, First People's Hospital of Kashgar, Kashgar, Xinjiang, China.
Department of Medicine, School of Medicine, Shihezi University, Shihezi, China.
Lung. 2025 Jun 16;203(1):69. doi: 10.1007/s00408-025-00824-4.
Macrophage polarization is essential for inflammatory regulation in COPD. The precise role of BPI Fold-Containing Family B Member 4 (BPIFB4) in regulating the inflammatory processes underlying COPD pathogenesis remains to be fully elucidated. This investigation seeks to clarify how BPIFB4 modulates macrophage polarization by activating the phosphoinositide 3-kinase (PI3K)-AKT1 signaling pathway, thereby influencing inflammatory progression in COPD.
In a COPD mouse model induced by cigarette smoke (CS) and lipopolysaccharide (LPS) and in cigarette smoke extract (CSE)-treated THP-1 cells, BPIFB4 was overexpressed or silenced. Bronchoalveolar lavage fluid, lung tissues, and serum were collected. qPCR and western blots assessed BPIFB4 and PI3K-AKT1 pathway expression in lung tissues and THP-1 cells. Flow cytometry evaluated M1/M2 macrophage polarization, and enzyme-linked immunosorbent assay (ELISA) measured related cytokine levels.
The results demonstrated how BPIFB4 gene silencing resulted in more pronounced lung tissue and functional damage compared to BPIFB4 overexpression, alongside an elevated presence of M1 macrophages and associated pro-inflammatory factors. In contrast, BPIFB4 overexpression in both COPD mice and CSE-treated THP-1 cells significantly enhanced p-AKT1 and p-PI3K levels while reducing the number of M1 macrophages. In addition, inhibition of the PI3K-AKT1 pathway reversed these effects, resulting in a marked increase in M1 macrophages and their associated cytokines.
BPIFB4 overexpression alleviates M1 macrophage polarization by activating the PI3K-AKT1 pathway, thereby reducing lung tissue damage and dysfunction in COPD mice.
巨噬细胞极化对于慢性阻塞性肺疾病（COPD）的炎症调节至关重要。含BPI折叠结构域家族B成员4（BPIFB4）在调节COPD发病机制的炎症过程中的精确作用仍有待充分阐明。本研究旨在阐明BPIFB4如何通过激活磷酸肌醇3-激酶（PI3K）-AKT1信号通路来调节巨噬细胞极化，从而影响COPD的炎症进展。
在香烟烟雾（CS）和脂多糖（LPS）诱导的COPD小鼠模型以及经香烟烟雾提取物（CSE）处理的THP-1细胞中，对BPIFB4进行过表达或沉默。收集支气管肺泡灌洗液、肺组织和血清。采用qPCR和蛋白质免疫印迹法评估肺组织和THP-1细胞中BPIFB4和PI3K-AKT1通路的表达。通过流式细胞术评估M1/M2巨噬细胞极化，酶联免疫吸附测定（ELISA）检测相关细胞因子水平。
结果表明，与BPIFB4过表达相比，BPIFB4基因沉默导致更明显的肺组织和功能损伤，同时M1巨噬细胞及其相关促炎因子的含量升高。相反，在COPD小鼠和经CSE处理的THP-1细胞中，BPIFB4过表达均显著提高了p-AKT1和p-PI3K水平，同时减少了M1巨噬细胞的数量。此外，抑制PI3K-AKT1通路可逆转这些作用，导致M1巨噬细胞及其相关细胞因子显著增加。
BPIFB4过表达通过激活PI3K-AKT1通路减轻M1巨噬细胞极化，从而减少COPD小鼠的肺组织损伤和功能障碍。
