Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1

Background: Sepsis is a potentially fatal whole-body inflammation caused by severe infection. Hydrogen gas (H-2) 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). Materials and methods: Male institute of cancer research mice were subjected to sepsis by cecal ligation and puncture (CLP) with the presence or absence of H-2. Beginning at 1 and 6 h after CLP or sham operation, respectively, 2% H-2 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 H-2 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 H-2 on septic lung injury. Conclusions: H-2 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. (C) 2015 Elsevier Inc. All rights reserved.