Effect of Norwogonin in Alleviating Acute Hypobaric Hypoxia Induced Lung Tissue Injury by Activating Nrf2/HO-1 Signaling Pathway

OBJECTIVE To investigate the protective effects and potential mechanisms of norwogonin in ameliorating acute hypobaric hypoxia(AHH) induced lung tissue injury in mice.

METHODS  Seventy-eight male BALB/c mice were randomly divided into 6 groups: the normal control group, the AHH group, the rutin group, and the low-, medium-, and high-dose groups of norwogonin. Mice in the normal control group and AHH group were intraperitoneally injected with normal saline, and the administration groups were intraperitoneally injected with rutin(200 mg·kg⁻¹) and low-, medium-, and high-dose of norwogonin(50, 100, 200 mg·kg⁻¹). The mouse model of AHH lung injury was established by exposure to an altitude of 8000 m animal experimentation chamber for 24 h. Pathological changes in mice lungs were evaluated using HE staining. The levels of H₂O₂, malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione(GSH) and the contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-6(IL-6) in lung tissue were detected using commercial kits. The levels of hypoxia-related proteinshypoxia-inducible factor-1α(HIF-1α) and vascular endothelial growth factor(VEGF), antioxidative stress-related proteinsnuclear factor erythroid 2-related factor 2(Nrf2) and heme oxygenase-1(HO-1), inflammation-related proteinsnuclear factor-κB(NF-κB) and TNF-α, and apoptosis-related proteinsB-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), and cleaved cysteine-aspartic acid caspase-3(Cleaved caspase-3) in lung tissues were detected by Western blotting. AutoDock software was used to perform molecular docking.

RESULTS  Compared to the AHH group, norwogonin administration remarkably decreased the water content and pathological changes in lung tissues, reduced the levels of H₂O₂, MDA, IL-1β, TNF-α and IL-6, and elevated SOD activity and GSH level, downregulated the expression levels of HIF-1α, VEGF, NF-κB, TNF-α, Bax and Cleaved caspase-3 proteins, upregulated the Nrf2, HO-1, Bcl-2 protein expression, and reduced the Bax/Bcl-2 ratio. Molecular docking results indicated that norwogonin exhibited strong binding abilities with Nrf2 and HO-1.

CONCLUSION  Norwogonin alleviates oxidative stress, reduces inflammatory responses, and inhibits apoptosis by activating Nrf2/HO-1 signaling pathway, thereby improving AHH induced lung tissue injury in mice.