[Vitamin D analogues activate vitamin D receptor/glutathione peroxidase 4 pathway to improve ventilator-induced lung injury in mice].

Objective: To investigate the role of vitamin D analogue paricalcitol in activating vitamin D receptor/glutathione peroxidase 4 (VDR/GPX4) pathway in ventilator-induced lung injury (VILI).

Methods: Twenty-four male C57BL/6J mice were randomly divided into control group, high tidal volume (HVT) induced VILI model group (HVT group), paricalcitol control group (P group), and paricalcitol pretreatment group (P+HVT group), with 6 mice in each group. The mice were endotracheal intubated and ventilated at 40 mL/kg tidal volume to prepare VILI model, while those in the control group were intubated without ventilation. The mice in the P+HVT group were intraperitoneally injected with paricalcitol 0.2 μg/kg once a day 1 week before modeling, while those in the P group were intraperitoneally injected paricalcitol 0.2 μg/kg once a day for 1 week before the experiment. After ventilation for 4 hours, the mice were sacrificed for lung tissue collection. Lung injury was evaluated by wet/dry (W/D) ratio, hematoxylin-eosin (HE) staining and Masson staining. The expressions of VDR and GPX4 were determined by Western blotting and immunohistochemistry. Malondialdehyde (MDA) and glutathione (GSH) contents were determined by micro method.

Results: After HVT for 4 hours, compared with the control group, lung injury score and W/D ratio were significantly higher (lung injury score: 0.430±0.035 vs. 0.097±0.025, lung W/D ratio: 4.860±0.337 vs. 3.653±0.332, both P < 0.05), collagen fiber deposition was significantly increased, the content of MDA in lung tissue was significantly increased (nmol/g: 212.420±8.757 vs. 97.073±5.308, P < 0.05), GSH content and the protein expressions and immunoreactive score (IRS) of VDR and GPX4 were significantly decreased [GSH (μg/g): 44.229±1.690 vs. 70.840±0.781; VDR protein (VDR/GAPDH): 0.518±0.029 vs. 0.762±0.081, GPX4 protein (GPX4/GAPDH): 0.452±0.032 vs. 0.649±0.034; IRS score: VDR was 4.168±0.408 vs. 10.167±0.408, GPX4 was 4.333±1.033 vs. 10.333±0.516; all P < 0.05], which meant that the mice in HVT group showed obvious lung injury. After VDR was activated by paricalcitol, compared with the HVT group, lung injury score and W/D ratio were significantly decreased (lung injury score: 0.220±0.036 vs. 0.430±0.035, lung W/D ratio: 4.015±0.074 vs. 4.860±0.337, both P < 0.05), collagen fiber deposition was reduced, MDA content in lung tissue was decreased (nmol/g: 123.840±8.082 vs. 212.420±8.757, P < 0.05), GSH content and the protein expressions and IRS score of VDR and GPX4 were significantly up-regulated [GSH (μg/g): 63.094±0.992 vs. 44.229±1.690; VDR protein (VDR/GAPDH): 0.713±0.056 vs. 0.518±0.029, GPX4 protein (GPX4/GAPDH): 0.605±0.008 vs. 0.452±0.032; IRS score: VDR was 9.000±0.632 vs. 4.168±0.408, GPX4 was 8.833±0.408 vs. 4.333±1.033; all P < 0.05], which meant that lung injury in P+HVT group was significantly improved.

Conclusion: Vitamin D analogue paricalcitol ameliorates pulmonary oxidation-reduction imbalance by activating the VDR/GPX4 pathway, thereby alleviating VILI.