7-Hydroxyethyl Chrysin Alleviates High Altitude Pulmonary Edema via Activation of the PI3K/AKT Signaling Pathway

Background: High-altitude pulmonary edema (HAPE) is a severe and potentially fatal complication without effective and safe measures. 7-hydroxyethyl chrysin (7-HEC) is a derivative of chrysin and exhibits excellent anti-hypoxia activities. The objective of this study was to investigate the protective effect and mechanism of 7-HEC against HAPE. Methods: The HAPE rat model was established using a hypobaric hypoxic cabin. The lung water content (LWC) and pulmonary microvascular permeability were measured, and the pathological changes of lung tissue were assessed by HE staining. The arterial blood gas indexes and routine blood indexes were measured. The levels of oxidative stress, inflammatory, energy metabolism and endothelial function markers in lung tissue or serum were quantified by commercial kits. qRT-PCR and Western blotting were employed to analyze the expressions of inflammatory and permeability associated genes and proteins. Network pharmacology and molecular docking were performed to reveal the pivotal targets of 7-HEC against HAPE and underlying mechanisms. Results: 7-HEC treatment reduced the LWC, attenuated pulmonary microvascular hyperpermeability, and improved lung tissue pathology in HAPE rats. Moreover, 7-HEC treatment normalized HAPE-induced changes in arterial blood gas and routine blood parameters. In addition, 7-HEC treatment significantly inhibited oxidative stress and inflammation, suppressed the energy metabolism dysfunction, and maintained the endothelial function. PI3K/AKT signaling pathway was identified as the core pathway for 7-HEC against HAPE by the results of network pharmacology analysis, molecular docking and Western blotting. Furthermore, LY294002, a selective PI3K/AKT inhibitor, significantly attenuated the protective effects of 7-HEC against HAPE. Conclusion: These findings indicate that 7-HEC may mitigate HAPE by activating the PI3K/AKT signaling pathway and could serve as an effective agent for preventing HAPE.