Protective role of nuclear factor erythroid 2-related factor 2 in the hemorrhagic shock-induced inflammatory response

Zhao,Haige; Hao,Sijing; Xu,Hongfei; Ma,Liang; Zhang,Zheng; Ni,Yiming; Yu,Luyang

doi:10.3892/ijmm.2016.2507

Protective role of nuclear factor erythroid 2-related factor 2 in the hemorrhagic shock-induced inflammatory response

Authors:
- Haige Zhao
- Sijing Hao
- Hongfei Xu
- Liang Ma
- Zheng Zhang
- Yiming Ni
- Luyang Yu
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Affiliations: Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China, Eye Center of the Affiliated Second Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
Published online on: February 25, 2016 https://doi.org/10.3892/ijmm.2016.2507
Pages: 1014-1022
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hemorrhagic shock (HS) following trauma or major surgery significantly contributes to mortality. However, the mechanisms through which HS activates the inflammatory response are not yet fully understood. Nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2), a bZIP transcription factor, is a master regulator of robust cytoprotective defenses. The present study investigated the role of Nrf2 in the pathophysiology of HS. Nrf2 expression in peripheral leukocytes obtained from patients with surgery-associated hemorrhage subjected to resuscitation treatment (termed HS patients) or healthy donors was examined by RT-qPCR. A marked increase in Nrf2 expression was detected in the leukocytes obtained from the HS patients, which indicates a correlation between Nrf2 expression and the development of HS. Wild-type (WT; Nrf2+/+) and Nrf2-deficient [Nrf2-/- or Nrf2‑knockout (KO)] mice were subjected to surgery to induce HS. Systemic inflammation was significantly elevated in the Nrf2-KO mice compared with the WT mice following HS, as assessed by an increase in serum cytokine levels [interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1β], as well as high-mobility group box 1 protein (HMGB1) expression. The Nrf2-KO mice exhibited more severe lung and liver injury following HS as evidenced by increased tissue damage, increased myeloperoxidase (MPO) activity and the increased production of pro-inflammatory cytokines. Additionally, Nrf2 deficiency augmented cytokine production induced by the exposure of peritoneal mouse macrophages to lipopolysaccharide (LPS) following HS. Taken together, these results suggest that Nrf2 is a critical host factor which limits immune dysregulation and organ injury following HS.

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