1,25-(OH)2D3 improves SD rats high-altitude pulmonary edema by inhibiting ferroptosis and ferritinophagy in alveolar epithelial cells

Background

This study investigates the protective effects and potential mechanisms of 1,25-(OH)₂D₃ against high-altitude pulmonary edema (HAPE).

Methods

Hypoxia-induced rats were administered 1,25-(OH)₂D₃ for 24, 48, and 72 hours, and we observed lung tissue injury and pulmonary edema. Immunohistochemistry (IHC) and Western blot analyses were employed to analyze the expression of markers associated with ferroptosis and ferritinophagy in rat lungs. Metabolomics analysis was conducted to investigate changes in serum lipid metabolites. We validated the mechanism of action of 1,25-(OH)₂D₃ in type II alveolar epithelial cells induced by hypoxia.

Results

Our results demonstrated that hypoxic exposure significantly altered sodium-water transport in the lungs, leading to edema formation. The degree of pulmonary edema was most pronounced at 48 hours of hypoxi. Treatment with 1,25-(OH)₂D₃ improved lung function and reduced the degree of pulmonary edema in hypoxic rats. Hypoxia-induced increases in 4-HNE and MDA levels in the lungs, along with iron accumulation, were observed. Hypoxia also resulted in elevated levels of NCOA4, LC3Ⅱ, and FTH1 proteins in the lungs. Furthermore, treatment with 1,25-(OH)₂D₃ significantly inhibited ferroptosis and ferritinophagy in the lungs after hypoxia. The levels of lipid metabolites, such as L-Aspartic acid and L-Fucose, were significantly elevated in the serum of hypoxic rats. After 1,25-(OH)₂D₃ treatment, these levels exhibited a significant reduction.

Conclusion

In hypoxic type II alveolar epithelial cells, 1,25-(OH)₂D₃ improved hypoxia-induced sodium-water transport, ferroptosis, and ferritinophagy, which were reversed by the autophagy agonist Rapamycin.By modulating ferroptosis and ferritinophagy, 1,25-(OH)₂D₃ mitigated the deleterious effects of hypoxia on pulmonary function.