Hydrogen Gas Protects Against Intestinal Injury in Wild Type But Not NRF2 Knockout Mice With Severe Sepsis by Regulating HO-1 and HMGB1 Release

• Published in: Shock (Augusta, Ga.) Ga.), 2017-09, Vol.48 (3), p.364-370
• Main Authors: Yu, Yang, Yang, Yongyan, Bian, Yingxue, Li, Yuan, Liu, Lingling, Zhang, Hongtao, Xie, Keliang, Wang, Guolin, Yu, Yonghao
• Format: Article
• Language: English
• Subjects: Animals; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - secretion; HMGB1 Protein - genetics; HMGB1 Protein - secretion; Hydrogen - pharmacology; Intestinal Diseases - genetics; Intestinal Diseases - metabolism; Intestinal Diseases - pathology; Intestinal Diseases - prevention & control; Intestines - injuries; Intestines - metabolism; Intestines - pathology; Membrane Proteins - genetics; Membrane Proteins - secretion; Mice; Mice, Knockout; NF-E2-Related Factor 2 - deficiency; Oxidative Stress - drug effects; Oxidative Stress - genetics; Sepsis - drug therapy; Sepsis - genetics; Sepsis - metabolism; Sepsis - pathology; Severity of Illness Index
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/SHK.0000000000000856

ABSTRACTThe 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 groupssham, 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.