Hydrogen inhalation ameliorates ventilator-induced lung injury

Abstract

IntroductionMechanical ventilation (MV) can provoke oxidative stress and an inflammatory response, and subsequently cause ventilator-induced lung injury (VILI), a major cause of mortality and morbidity of patients in the intensive care unit. Inhaled hydrogen can act as an antioxidant and may be useful as a novel therapeutic gas. We hypothesized that, owing to its antioxidant and anti-inflammatory properties, inhaled hydrogen therapy could ameliorate VILI.MethodsVILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg without positive end-expiratory pressure, FiO2 0.21). The mice were randomly assigned to treatment groups and subjected to VILI with delivery of either 2% nitrogen or 2% hydrogen in air. Sham animals were given same gas treatments for two hours (n = 8 for each group). The effects of VILI induced by less invasive and longer exposure to MV (tidal volume of 10 ml/kg, 5 hours, FiO2 0.21) were also investigated (n = 6 for each group). Lung injury score, wet/dry ratio, arterial oxygen tension, oxidative injury, and expression of pro-inflammatory mediators and apoptotic genes were assessed at the endpoint of two hours using the high-tidal volume protocol. Gas exchange and apoptosis were assessed at the endpoint of five hours using the low-tidal volume protocol.ResultsVentilation (30 ml/kg) with 2% nitrogen in air for 2 hours resulted in deterioration of lung function, increased lung edema, and infiltration of inflammatory cells. In contrast, ventilation with 2% hydrogen in air significantly ameliorated these acute lung injuries. Hydrogen treatment significantly inhibited upregulation of the mRNAs for pro-inflammatory mediators and induced antiapoptotic genes. In the lungs treated with hydrogen, there was less malondialdehyde compared with lungs treated with nitrogen. Similarly, longer exposure to mechanical ventilation within lower tidal volume (10 mg/kg, five hours) caused lung injury including bronchial epithelial apoptosis. Hydrogen improved gas exchange and reduced VILI-induced apoptosis.ConclusionsInhaled hydrogen gas effectively reduced VILI-associated inflammatory responses, at both a local and systemic level, via its antioxidant, anti-inflammatory and antiapoptotic effects.

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

“…Our laboratory has extensively explored the application of hydrogen for the treatment of various diseases (7,9,33), including acute lung injuries (15,23,24). Hydrogen is a selective radical scavenger for hydroxyl radicals and peroxynitrite (14,37), and this aspect of hydrogen's chemistry may explain its therapeutic effects.…”

“…After gas exposure, the animals were anesthetized, and lung function was assessed by analysis of blood gases on a fraction of inspired oxygen of 1.0 in blood drawn from the abdominal aorta. The left lung was used for bronchoalveolar lavage, as described previously (15). The pleural effusion volume was measured immediately after opening the chest cavity.…”

“…Hydrogen may also act as a gaseous signaling molecule, similar to nitric oxide (19). Our laboratory has explored the application of inhaled hydrogen for acute lung injuries and found that treatment with inhaled hydrogen mitigates mechanical ventilation-induced lung injury (15) and transplant-induced lung ischemia-reperfusion injury (23,24). We discovered that inhaled hydrogen gas induces heme oxygenase (HO)-1 in the donor lungs before transplantation and leads to excellent preconditioning of lung allografts and improved transplant outcomes (23).…”

The hydrogen molecule as antioxidant therapy: clinical application in hemodialysis and perspectives

“…Thereafter, accumulating evidence from animal studies indicated a protective effect of H 2 pretreatment on the progression of organ damage in various types of disease models , such as ischemia-induced injury and dysfunction of the brain [22,33,39,55,59,[62][63][64], heart [34,45,59,65], liver [30], retina [41], and kidney [59,60]; stress-induced hippocampus dysfunction [38]; cisplatinum nephropathy [37,44]; transplanted intestinal graft [31,47]; corneal alkali burn [51]; ouabain-induced auditory neuropathy [66]; lung injury by oxygen toxicity [43,46]; paraquat [52]; extensive burns [54]; chronic allograft nephropathy [48]; and radiation injuries in various organs [49,50,55,68,69]. In Parkinson's disease [36,40] and Alzheimer's disease models [42], H 2 ameliorates neurodegenerative changes in the brain.…”

“…In previous studies, H 2 was administered by inhalation [22,30,31,34,37,45,46,56,[62][63][64]66] or dissolved in water [22, 32-44, 47-55, 57-61, 65, 67-69]. Irrespective of the administration route, H 2 pretreatment could suppress oxidation, inflammation, and apoptosis while enhancing antioxidant reactions in those models.…”