Oncotarget

Research Papers:

Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome

Yao-Li Cui, Li-Hua Qiu, Shi-Yong Zhou, Lan-Fang Li, Zheng-Zi Qian, Xian-Ming Liu, Hui-Lai Zhang _, Xiu-Bao Ren and Yong-Qiang Wang

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Oncotarget. 2017; 8:56980-56990. https://doi.org/10.18632/oncotarget.18252

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Abstract

Yao-Li Cui1,2, Li-Hua Qiu1, Shi-Yong Zhou1, Lan-Fang Li1, Zheng-Zi Qian1, Xian-Ming Liu1, Hui-Lai Zhang1, Xiu-Bao Ren3 and Yong-Qiang Wang2

1Department 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

2Department 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

3Department 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: [email protected]

Xiu-Bao Ren, email: [email protected]

Yong-Qiang Wang, email: [email protected]

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.


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