title: Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1.
abstract: BACKGROUND
  Sepsis is a potentially fatal whole-body inflammation caused by severe infection. Hydrogen gas (H2) is effective for treating sepsis. In this study, we hypothesized that the protective function of H2 in mice with septic lung injury occurred through the activation of heme oxygenase 1 (HO-1) and its upstream regulator nuclear factor-erythroid 2 p45-related factor 2 (Nrf2).
  
  
  METHODS
  Male institute of cancer research mice were subjected to sepsis by cecal ligation and puncture (CLP) with the presence or absence of H2. Beginning at 1 and 6 h after CLP or sham operation, respectively, 2% H2 was inhaled for 1 h. We intraperitoneally injected the HO-1 inhibitor zinc protoporphyrin IX (40 mg/kg) 1 h before CLP. To assess the severity of septic lung injury, we observed the 7-d survival rate, wet/dry weight ratio of lung, lung histopathologic score, oxygenation index, and so forth. Serum and homogenates from the lung, liver, and kidney were acquired for measuring the levels of high-mobility group box 1 (HMGB1) at 6, 12, and 24 h after CLP or sham operation. Furthermore, the protein and messenger RNA expression of Nrf2, HO-1, and HMGB1 was measured at 6, 12, and 24 h.
  
  
  RESULTS
  Septic mice had a lower survival rate and more severe lung injury compared with the sham group. However, therapy with H2 increased the survival rate and alleviated the severity of lung injury, reduced the HMGB1 level, and increased the HO-1 and Nrf2 levels in septic mice. Moreover, the HO-1 inhibitor zinc protoporphyrin IX significantly eliminated the protective effect of H2 on septic lung injury.
  
  
  CONCLUSIONS
  H2 plays a significant role in regulating the release of the inflammatory cytokine HMGB1 in septic mice, which is partially mediated through the activation of HO-1 as a downstream molecule of Nrf2.
authors.affiliation: Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, China; Tianjin Institute of Anesthesiology, Tianjin, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, China; Tianjin Institute of Anesthesiology, Tianjin, China. Electronic address: xiekeliang2009@hotmail.com.
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, China; Tianjin Institute of Anesthesiology, Tianjin, China.
authors.forename: Hongguang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, China; Tianjin Institute of Anesthesiology, Tianjin, China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, China; Tianjin Institute of Anesthesiology, Tianjin, China. Electronic address: yuyonghao@126.com.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006859:Hydrogen / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009195:Peroxidase / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D024243:HMGB1 Protein; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006859:Hydrogen; D009195:Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Acute lung injury; Heme oxygenase 1; High-mobility group box 1; Hydrogen gas; Sepsis