Ezetimibe pretreatment attenuates early ischemia-reperfusion injury in a rat model of lung transplantation.

Abstract

Ischemia-reperfusion injury (IRI) after transplantation causes early and late graft dysfunction. Ezetimibe (Eze) is a lipid-reducing agent that has been reported to attenuate oxidative stress and inflammation in non-pulmonary models of ischemia-reperfusion. We examined its effect in a rat lung transplantation model. Lewis rats (n = 8/group) underwent left lung transplantation without pretreatment (LT) or with Eze pretreatment of the donor (LT-D), recipient (LT-R), or both (LT-DR). Eze (1 mg/kg) was given orally three times weekly for 2 weeks, and donor lungs were transplanted after 6 h of cold storage. Graft gas exchange, histology, inflammation, and apoptosis were assessed after 2 h of reperfusion. Graft PaO2/FiO2, measured with the contralateral hilum clamped, differed among the groups (176.8 ± 149.6, 265.1 ± 124.3, 321.9 ± 130.2, and 412.6 ± 142.3 mmHg in LT, LT-D, LT-R, and LT-DR; p = 0.015) and was significantly higher than in LT only in LT-DR. All treatment groups had lower lung injury scores than LT (16.62 ± 0.65 vs 12.25 ± 0.78, 10.95 ± 0.46, and 10.72 ± 0.40; p < 0.001). Plasma inflammatory cytokines and lung tissue myeloperoxidase were also lower in the treatment groups, and TUNEL positivity was significantly lower only in LT-DR. In conclusion, Eze pretreatment attenuated early IRI in a rat model of lung transplantation. Because the AMPK/Nrf2 pathway and direct indices of oxidative stress were not measured, the mechanism of this protection remains undetermined, and the findings are confined to the first 2 h after reperfusion.

Key Findings

• Ezetimibe pretreatment improved graft gas exchange in a rat lung transplantation model, with the best results seen when both donor and recipient were treated.
• All ezetimibe treatment groups showed lower lung injury scores and reduced plasma inflammatory cytokines and lung tissue myeloperoxidase compared to untreated controls.
• Apoptosis, measured by TUNEL positivity, was significantly reduced only when both donor and recipient received ezetimibe pretreatment.

Clinical Significance

Citation

Kim Ha Eun, Bae Soo Han, Haam Seokjinet al.. Ezetimibe pretreatment attenuates early ischemia-reperfusion injury in a rat model of lung transplantation. Transplant immunology. 2026-Oct-17.