Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Kawamura, Tomohiro; Wakabayashi, Nobunao; Shigemura, Norihisa; Huang, Chien Sheng; Masutani, Kosuke; Tanaka, Yugo; Noda, Kentaro; Peng, Ximei; Takahashi, Toru; Billiar, Timothy R.; Okumura, Meinoshin; Toyoda, Yoshiya; Kensler, Thomas W.; Nakao, Atsunori

doi:10.1152/ajplung.00164.2012

Cited by 146 publications

(141 citation statements)

References 48 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…In a rat model of hyperoxic lung injury, H 2 reduced mRNA levels encoding several proinflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and intercellular adhesion molecule-1, in the lung. 40 H 2 inhalation significantly improved the survival rate and organ damage in a mouse model of cecal ligation and puncture-induced sepsis, 44 as well as zymosan-induced generalized inflammation.…”

Section: Discussionmentioning

confidence: 93%

“…The reduction of oxidative stress by H 2 may lead to various effects, including anti-inflammatory and antiapoptotic responses via changes in gene expression, 40 signal transduction, [41][42][43] and mitochondrial membrane potential, 11,37 although whether H 2 has a mode of action independent of its antioxidative properties is unknown. In a rat model of hyperoxic lung injury, H 2 reduced mRNA levels encoding several proinflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and intercellular adhesion molecule-1, in the lung.…”

Section: Discussionmentioning

confidence: 99%

“…40 Inhalation of H 2 also reduced infarct size in a canine model of cardiac ischemia/reperfusion injury via opening of the mitochondrial K ATP channels followed by inhibition of mitochondrial permeability transition pores. 11 We recognize several limitations of our study.…”

mentioning

confidence: 95%

See 2 more Smart Citations

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

et al. 2014

View full text Add to dashboard Cite

Background-We have previously shown that hydrogen (H 2 ) inhalation, begun at the start of hyperoxic cardiopulmonary resuscitation, significantly improves brain and cardiac function in a rat model of cardiac arrest. Here, we examine the effectiveness of this therapeutic approach when H 2 inhalation is begun on the return of spontaneous circulation (ROSC) under normoxic conditions, either alone or in combination with targeted temperature management (TTM). Methods and Results-Rats were subjected to 6 minutes of ventricular fibrillation cardiac arrest followed by cardiopulmonary resuscitation. Five minutes after achieving ROSC, post-cardiac arrest rats were randomized into 4 groups: mechanically ventilated with 26% O 2 and normothermia (control); mechanically ventilated with 26% O 2 , 1.3% H 2 , and normothermia (H 2 ); mechanically ventilated with 26% O 2 and TTM (TTM); and mechanically ventilated with 26% O 2 , 1.3% H 2 , and TTM (TTM+H 2 ). Animal survival rate at 7 days after ROSC was 38.4% in the control group, 71.4% in the H 2 and TTM groups, and 85.7% in the TTM+H 2 group. Combined therapy of TTM and H 2 inhalation was superior to TTM alone in terms of neurological deficit scores at 24, 48, and 72 hours after ROSC, and motor activity at 7 days after ROSC. Neuronal degeneration and microglial activation in a vulnerable brain region was suppressed by both TTM alone and H 2 inhalation alone, with the combined therapy of TTM and H 2 inhalation being most effective. Conclusions-H 2 inhalation was beneficial when begun after ROSC, even when delivered in the absence of hyperoxia.Combined TTM and H 2 inhalation was more effective than TTM alone. (Circulation. 2014;130:2173-2180.)

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In a recent study, Fernandez-Gonzalez and colleagues (42) could now show that constitutive lungspecific overexpression of the carbon monoxide-generating enzyme heme oxygenase 1 (HO-1) confers vasculoprotective effects in a murine model of hyperoxia-induced bronchopulmonary dysplasia, in that pulmonary inflammation, arterial remodeling, and pulmonary edema were markedly improved. In adult lungs, Kawamura and colleagues (73) found the detrimental effects of hyperoxia on lung injury, inflammation, and edema to be markedly alleviated in animals inhaling 2% hydrogen, and this effect was associated with an increased expression of HO-1. Notably, protection by hydrogen gas inhalation was alleviated in mice deficient in the main transcription factor for antioxidative genes, Nrf2, which regulates HO-1 expression, suggesting that hydrogen gas alleviates hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1.…”

Section: Pulmonary Endothelial Barrier Functionmentioning

confidence: 99%

Novel regulators of endothelial barrier function

Mehta

Ravindran

Kuebler

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

109

View full text Add to dashboard Cite

Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively.

show abstract

“…When H 2 is administered in inflammatory conditions, it affects intracellular signals, including NF-jB [8,9], ERK [9,10], p38 [9,10], JNK [8][9][10], and Nrf2 [11], and also the expression of a large number of genes, including inflammatory cytokines. However, the mechanism of these actions is unknown.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents

et al. 2015

View full text Add to dashboard Cite

Molecular hydrogen (H2) is an agent with potential applications in oxidative stress-related and/or inflammatory disorders. H2 is usually administered by inhaling H2-containing air (HCA) or by oral intake of H2-rich water (HRW). Despite mounting evidence, the molecular mechanism underlying the therapeutic effects and the optimal method of H2 administration remain unclear. Here, we investigated whether H2 affects signaling pathways and gene expression in a dosage- or dose regimen-dependent manner. We first examined the H2 concentrations in blood and organs after its administration and found that oral intake of HRW rapidly but transiently increased H2 concentrations in the liver and atrial blood, while H2 concentrations in arterial blood and the kidney were one-tenth of those in the liver and atrial blood. In contrast, inhalation of HCA increased H2 equally in both atrial and arterial blood. We next examined whether H2 alters gene expression in normal mouse livers using DNA microarray analysis after administration of HCA and HRW. Ingenuity Pathway Analysis revealed that H2 suppressed the expression of nuclear factor-kappa B (NF-κB)-regulated genes. Western blot analysis showed that H2 attenuated ERK, p38 MAPK, and NF-κB signaling in mouse livers. Finally, we evaluated whether the changes in gene expression were influenced by the route of H2 administration and found that the combination of both HRW and HCA had the most potent effects on signaling pathways and gene expression in systemic organs, suggesting that H2 may act not only through a dose-dependent mechanism but also through a complex molecular network.

show abstract

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Cited by 146 publications

References 48 publications

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

Novel regulators of endothelial barrier function

Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents

Contact Info

Product

Resources

About