S100A4 Promotes Alveolar Epithelial Remodeling and Airway Inflammation in Asthma by Inducing Epithelial-Mesenchymal Transition.

Objective: To investigate the expression of calcium-binding protein S100A4 in asthmatic alveolar type II epithelial cells (AT2) and its functional mechanism in regulating cell phenotype and inflammatory secretion. Methods: The GSE213085 single-cell dataset was analyzed via bioinformatics to examine the expression distribution of S100A4 in alveolar type II epithelial cells (AT2). An OVA-induced asthmatic mouse model was established. The expression abundance of S100A4 was validated using RT-qPCR, WB, immunohistochemistry, and ELISA. A549 and MLE-12 cell lines were cultured ex vivo and treated with exogenous recombinant S100A4 protein. The expression of epithelial-mesenchymal transition (EMT)-related markers (E-cadherin, α-SMA, Vimentin) was detected. Cell migration capacity was assessed by scratch wound and Transwell assays. The levels of alarmins (IL-25, IL-33, TSLP) and the pro-inflammatory cytokine IL-6 in the culture supernatant were measured. Results: Consistent findings from bioinformatics analysis and animal experiments demonstrated that S100A4 expression was significantly upregulated in AT2 cells and lung tissue homogenates from the asthmatic group. Levels of IL-6 and alarmins were concurrently elevated in the bronchoalveolar lavage fluid of asthmatic mice. Furthermore, ex vivo experiments indicated that S100A4 could directly induce the secretion of alarmins IL-25, IL-33, and TSLP from A549 and MLE-12 lung epithelial cells. Additionally, exogenous S100A4 induced significant EMT remodeling in A549 and MLE-12 cells, characterized by downregulation of the epithelial marker E-cadherin, upregulation of the mesenchymal markers α-SMA and Vimentin, and accompanied by enhanced migratory activity. Conclusion: The abnormally elevated expression of S100A4 in asthmatic AT2 cells can induce an EMT phenotypic switch in AT2 cells and promote alarmin secretion. S100A4 may be an important pathological factor contributing to aggravated airway inflammation and structural remodeling in asthma, providing a new theoretical basis and a potential intervention target for the precise treatment of asthma.