Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome

// Yao-Li Cui 1, 2 , Li-Hua Qiu 1 , Shi-Yong Zhou 1 , Lan-Fang Li 1 , Zheng-Zi Qian 1 , Xian-Ming Liu 1 , Hui-Lai Zhang 1 , Xiu-Bao Ren 3 and Yong-Qiang Wang 2 1 Department of Lymphoma, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China 2 Department of Intensive Care Unit and Key Laboratory for Critical Care Medicine of The Ministry of Health, Emergency Medicine Research Institute, Tianjin First Center Hospital, Tianjin 300192, China 3 Department of Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy and Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China Correspondence to: Hui-Lai Zhang, email: zhlwgq@126.com Xiu-Bao Ren, email: renxiubao1111@163.com Yong-Qiang Wang, email: wangyongqiang1100@163.com Keywords: multiple organ dysfunction syndrome, necroptosis, necrosome, high-mobility group box 1, mixed-lineage kinase domain-like Received: March 24, 2017      Accepted: April 17, 2017      Published: May 29, 2017 ABSTRACT 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.