MFGE8通过骨形态发生蛋白（BMP）信号通路调控人肺微血管内皮细胞（HLMECs）的内皮-间质转化（EndoMT）以及急性肺损伤中的纤维化。

MFGE8 regulates the EndoMT of HLMECs through the BMP signaling pathway and fibrosis in acute lung injury.

作者信息

Shi Qingqiang, Liu Huang, Wang Hanghang, Tang Ling, Di Qi, Wang Daoxin

机构信息

The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.

出版信息

Respir Res. 2025 Apr 13;26(1):142. doi: 10.1186/s12931-025-03215-8.

BACKGROUND

To investigate the effects and mechanisms of MFGE8 on LPS-induced endothelial-to-mesenchymal transition (EndoMT) and pulmonary fibrosis in human lung microvascular endothelial cells (HLMECs) and a mouse model of acute lung injury.

METHODS

Serum MFGE8 levels were compared between ARDS patients and controls. In vitro, HLMECs were treated with LPS, siRNA targeting MFGE8, and recombinant human MFGE8 (rhMFGE8).HLMEC morphology, invasion, migration, and EndoMT markers (CD31, ɑ-SMA) were evaluated. BMP/Smad1/5-Smad4 signaling and Snail expression were assessed via immunofluorescence, western blotting, and qRT-PCR. In vivo, rhMFGE8 effects on pulmonary fibrosis and EndoMT were analyzed in a mouse model of acute lung injury.

RESULTS

MFGE8 levels were significantly reduced in ARDS patients, with higher levels correlating to better survival. In vitro, rhMFGE8 improved HLMEC morphology, reduced invasion and migration, and attenuated LPS-induced EndoMT by increasing CD31 and decreasing α-SMA. MFGE8 knockdown increased BMP/Smad1/5-Smad4 signaling and Snail expression, while rhMFGE8 inhibited these effects. In vivo, rhMFGE8 ameliorated pulmonary fibrosis and EndoMT in mice.

CONCLUSIONS

MFGE8 regulates LPS-induced EndoMT in HLMECs via the BMP/Smad1/5-Smad4 pathway and protects against pulmonary fibrosis in acute lung injury, suggesting it as a therapeutic target for ALI and ARDS.

背景

研究牛奶脂肪球表皮生长因子8（MFGE8）对人肺微血管内皮细胞（HLMECs）中脂多糖（LPS）诱导的内皮-间充质转化（EndoMT）及肺纤维化的影响和机制，以及在急性肺损伤小鼠模型中的作用。

方法

比较急性呼吸窘迫综合征（ARDS）患者和对照组血清中MFGE8水平。体外实验中，用LPS、靶向MFGE8的小干扰RNA（siRNA）和重组人MFGE8（rhMFGE8）处理HLMECs。评估HLMECs的形态、侵袭、迁移及EndoMT标志物（CD31、α-平滑肌肌动蛋白（α-SMA））。通过免疫荧光、蛋白质免疫印迹和定量逆转录聚合酶链反应（qRT-PCR）评估骨形态发生蛋白（BMP）/Smad1/5-Smad4信号通路和Snail表达。体内实验中，在急性肺损伤小鼠模型中分析rhMFGE8对肺纤维化和EndoMT的影响。

结果

ARDS患者的MFGE8水平显著降低，水平越高与生存率越高相关。体外实验中，rhMFGE8改善了HLMECs的形态，减少了侵袭和迁移，并通过增加CD31和降低α-SMA减轻了LPS诱导的EndoMT。敲低MFGE8增加了BMP/Smad1/5-Smad4信号通路和Snail表达，而rhMFGE8抑制了这些作用。体内实验中，rhMFGE8改善了小鼠的肺纤维化和EndoMT。