title: Protective role of nuclear factor erythroid 2-related factor 2 in the hemorrhagic shock-induced inflammatory response.
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.
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Haige
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Sijing
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: Eye Center of the Affiliated Second Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Luyang
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D012771:Shock, Hemorrhagic / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D051267:NF-E2-Related Factor 2