A novel preclinical model of cDCD lung transplantation with implications for necroptosis

Abstract

Abstract This study established a novel rat model that simulates controlled donation after circulatory death (cDCD) lung transplantation (LTx), and investigated necroptosis as a therapeutic target to improve graft quality using a three-phase experimental design. First, we established a model that reproduced the agonal phase in the donor (Phase I). Second, prolonged warm ischemic time progressively worsened graft function, as evidenced by reduced oxygenation, increased pulmonary edema, and increased necroptosis-related signals in pretransplant samples (Phase II). Accordingly, necrostatin-1 (Nec-1), an inhibitor of receptor-interacting protein kinase 1 (RIPK1), was administered during the pre-mortem, graft-flushing, and peri-transplant periods, which improved graft quality, reduced neutrophil infiltration after reperfusion, and decreased the ratio of phosphorylated mixed lineage kinase domain-like protein to total MLKL (pMLKL/MLKL) in pre-transplant samples, consistent with the attenuation of necroptosis-related signaling. These findings suggested that necroptosis-related signaling during the ischemic phase is associated with graft injury in cDCD LTx, and that RIPK1 inhibition may represent a potential therapeutic strategy for attenuating graft injury under prolonged warm ischemia.