Pre-B-cell colony enhancing factor regulates the alveolar epithelial sodium-water transport system through the ERK and AKT pathways.

The sodium-water transport system is crucial for alveolar fluid clearance. The pulmonary edema caused by extracorporeal circulation is mainly due to increased alveolar capillary permeability and reduced fluid clearance. We previously demonstrated that pre-B-cell colony enhancing factor (PBEF) increases alveolar capillary permeability and inhibits the sodium-water transport system. However, the specific mechanism by which PBEF inhibits the sodium-water transport system is unclear. In this study, we used HPAEpiC (alveolar type II epithelial cells) to construct an anoxia-reoxygenation model and simulate the extracorporeal circulation microenvironment. The impact of PBEF on the expression of genes and proteins implicated in sodium transport and its effect on the activation status of the ERK, P38, and AKT signaling pathways were explored in HPAEpiC by real-time fluorescent PCR and western blotting. Specific inhibitors were employed to verify the role of the three signaling pathways in the regulation of the sodium-water transport system. PBEF was substantially non-toxic to alveolar epithelial cells, inhibited the expression of ENaC, NKA, and AQP1, and affected the ERK, P38, and AKT signaling pathways. ERK pathway inhibitors attenuated PBEF-induced downregulation of EnaC, NKA, and AQP1, and increased NKA activity. P38 pathway inhibitors only attenuated PBEF-induced suppression of NKA expression. AKT pathway inhibitors potentiated the inhibitory effects of PBEF, reducing EnaC, AQP1, and NKA expression, as well as NKA activity. In conclusion, PBEF inhibited the sodium-water transport system by activation of ERK and suppression of AKT signaling.