Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome

Purpose: To investigate how necroptosisis, i.e. programmed necrosis, is involved in MODS, and to examine whether Nec-1, a specific necroptosis inhibitor, ameliorates multiorgan injury in MODS. Experimental Design: A model of MODS was established in six-week old SD rats using fracture trauma followed by hemorrhage. Control animals received sham surgery. Cell death form and necrosome formation were measured by fluorescence activated cell sorting and western blotting. MODS rats were randomly assigned to receive Nec-1 or saline with pretreatment and once daily. The first end-point was 72 hours survival. Organ injury and dysfunction, inflammatory cytokine levels, and necroptotic execution protein expression were also recorded. Results: Organ injury and dysfunction were significantly more severe in the MODS group than the sham group (all p < 0.01). Furthermore, MODS-induced liver, lung and kidney tissue injury was characterized by necroptosis rather than apoptosis, and accompanied by necrosome formation. Compared to MODS group, Nec-1 administration significantly improved 72 hours survival (p < 0.01). Nec-1 administration significantly reduced necroptosis-induced liver, lung and kidney injury and dysfunction, inhibited inflammatory cytokines production, inhibited release of necroptotic execution proteins such as high-mobility group box 1 and mixed-lineage kinase domain-like protein pseudokinase in MODS rats (all p < 0.01). Conclusions: These results suggest that necroptosis is involved the pathology of MODS. Further, a necroptotic inhibitor Nec-1 may be considered as an adjunct treatment for MODS.