title: Hydrogen Gas Protects Against Intestinal Injury in Wild Type But Not NRF2 Knockout Mice With Severe Sepsis by Regulating HO-1 and HMGB1 Release.
abstract: The intestine plays an important role in the pathogenesis of sepsis. Hydrogen gas (H2), which has anti-oxidative, anti-inflammatory, and anti-apoptotic effects, can be effectively used to treat septic mice. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive master switch that regulates the expression of antioxidant and protective enzymes. This study investigated the effects of 2% H2 on intestinal injuries and the underlying mechanisms in a mouse model of severe sepsis. Male Nrf2 knockout mice (Nrf2-KO) and wild-type (WT) mice were randomized into four groups: sham, sham+H2, cecal ligation and puncture (CLP), and CLP+H2. The survival rate was observed and recorded within 7 days, and pro-inflammatory cytokines (TNF-α, IL-6, HMGB1), anti-inflammatory cytokine (IL-10), antioxidant enzymes (superoxide dismutase, and catalase ), and oxidative products (MDA, 8-iso-PGF2α) were detected in the serum and intestine using an enzyme-linked immunosorbent assay. In addition, the protein and mRNA levels of heme oxygenase-1 (HO-1) and high mobility group box 1 (HMGB1) were measured by Western blotting and quantitative PCR, respectively. Immunofluorescence and immunohistochemistry were used to measure HMGB1 and HO-1 release into the intestine, respectively. The results showed that therapy with 2% H2 increased the survival rate, alleviated the injuries caused by oxidative stress and inflammation, reduced HMGB1 levels but increased HO-1 levels in WT septic mice, but not in Nrf2-KO mice. These data demonstrate that 2% H2 inhalation may be a promising therapeutic strategy for intestinal injuries caused by severe sepsis through the regulation of HO-1 and HMGB1 release. In addition, Nrf2 plays a key role in the protective effects of H2 against intestinal damage in this disease.
authors.affiliation: *Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China †Tianjin Institute of Anesthesiology, Tianjin, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Yang
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Bian
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Lingling
authors.initials: L
authors.lastname: Liu
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006859:Hydrogen / Q000494:pharmacology*; D007410:Intestinal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000293:injuries / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D006859:Hydrogen; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse