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.

Hydrogen gas inhalation protects against cutaneous ischaemia/reperfusion injury in a mouse model of pressure ulcer

“…In our study, H 2 treatment significantly up‐regulated the expression of Nrf2 and its downstream targets such as HO‐1, NQO1 and AKR1C1 in wound tissue and HUEVCs exposed to H 2 O 2 . Similar phenomena were also observed in previous studies of other organ I/R injury or other inflammatory diseases . Molecular hydrogen could attenuate intestinal injury in wild‐type but not NRF2‐knockout mice with severe sepsis by regulating HO‐1 expression .…”

“…Similar phenomena were also observed in previous studies of other organ I/R injury or other inflammatory diseases . Molecular hydrogen could attenuate intestinal injury in wild‐type but not NRF2‐knockout mice with severe sepsis by regulating HO‐1 expression . Therefore, hydrogen might activate the Nrf2/ARE pathway to restore the homoeostasis of cutaneous oxidation‐reduction system against I/R injury.…”

[Retracted] Protective Effects of Hydrogen on Myocardial Mitochondrial Functions in Septic Mice

“…Our previous investigations demonstrated increased survival and reduced injury and dysfunction in different organs (e.g., lungs, liver, kidney, and intestinal tract) in various septic models treated with H 2 inhalation [17][18][19]. In the present study, using a CLP model, we investigated whether HO-1 mediated the positive effects of H 2 on myocardial injury in a murine model of sepsis.…”

“…Another study demonstrated that inhalation of 2% H 2 could potentially alleviate intestinal damage caused by severe sepsis by regulating the release of HO-1 and high mobility group box 1 (HMGB1) [16]. Moreover, Nrf2 played a key role in the protective effect of H 2 against intestinal injury [17].…”

Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats

“…The main mechanisms of neonatal HIBI include oxidative stress, excitability, inflammation, and apoptosis [2]. Many researchers believe that similar to nitric oxide, hydrogen sulfide, and carbon monoxide, H 2 may be an important bioactive gas [30,31]. There are no reported side effects with H 2 , which may confer a unique advantage in disease prevention and treatment [31].…”