Inhibition of S100A12 Attenuates LPS-induced Endothelial Barrier Dysfunction in HPMECs through the JAK2/STAT3...

The calcium-binding protein S100A12 plays a pivotal role in the progression of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the underlying mechanisms are yet to be fully elucidated.

This study aimed to investigate the role of S100A12 in LPS-induced injury of human pulmonary microvascular endothelial cells (HPMECs) and its molecular regulatory mechanism.

An in vitro model of ALI/ARDS was established by lipopolysaccharide (LPS)-induced HPMECs. CCK-8, flow cytometry assay, and ELISA were used to detect the cell viability, apoptosis, and inflammation. The integrity of the endothelial barrier was assessed by tube formation assay and VE-cadherin and occludin protein levels. The molecular mechanism of S100A12 was analyzed by transcriptomics and validated using qRT-PCR and western blotting analyses.

S100A12 expression was significantly elevated in LPS-stimulated HPMECs, and S100A12 knockdown alleviated LPS-induced apoptosis, inflammation, and endothelial barrier dysfunction in HPMECs. Transcriptomic analysis revealed the potential gene network mapping regulated by LPS stimulation and S100A12 knockdown. Differentially expressed genes were significantly enriched in the JAK2/STAT3 signaling pathway as verified by western blotting analysis.

In summary, our findings demonstrate that S100A12 promotes LPS-induced pulmonary endothelial barrier dysfunction primarily through activation of the JAK2/STAT3 signaling pathway. This reveals a previously uncharacterized mechanism for S100A12 in ALI/ARDS pathogenesis and positions it as a potential therapeutic target for attenuating lung endothelial injury.

Our results suggested S100A12 to be significantly upregulated in LPS-induced HPMECs; inhibiting S100A12 can alleviate endothelial cell barrier dysfunction through the JAK2/STAT3 signaling pathway and thereby improve LPS-induced HPMECs injury.