Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan.
The Center for Molecular Hydrogen Medicine, Keio University, Tokyo, Japan.
Shock. 2020 Sep;54(3):377-385. doi: 10.1097/SHK.0000000000001459.
Hydrogen gas (H2) inhalation during hemorrhage stabilizes post-resuscitation hemodynamics, improving short-term survival in a rat hemorrhagic shock and resuscitation (HS/R) model. However, the underlying molecular mechanism of H2 in HS/R is unclear. Endothelial glycocalyx (EG) damage causes hemodynamic failure associated with HS/R. In this study, we tested the hypothesis that H2 alleviates oxidative stress by suppressing xanthine oxidoreductase (XOR) and/or preventing tumor necrosis factor-alfa (TNF-α)-mediated syndecan-1 shedding during EG damage.
HS/R was induced in rats by reducing mean arterial pressure (MAP) to 35 mm Hg for 60 min followed by resuscitation. Rats inhaled oxygen or H2 + oxygen after achieving shock either in the presence or absence of an XOR inhibitor (XOR-I) for both the groups. In a second test, rats received oxygen alone or antitumor necrosis factor (TNF)-α monoclonal antibody with oxygen or H2. Two hours after resuscitation, XOR activity, purine metabolites, cytokines, syndecan-1 were measured and survival rates were assessed 6 h after resuscitation.
H2 and XOR-I both suppressed MAP reduction and improved survival rates. H2 did not affect XOR activity and the therapeutic effects of XOR-I and H2 were additive. H2 suppressed plasma TNF-α and syndecan-1 expression; however, no additional H2 therapeutic effect was observed in the presence of anti-TNF-α monoclonal antibody.
H2 inhalation after shock stabilized hemodynamics and improved survival rates in an HS/R model independent of XOR. The therapeutic action of H2 was partially mediated by inhibition of TNF-α-dependent syndecan-1 shedding.
在出血期间吸入氢气（H2）可稳定复苏后血液动力学，改善大鼠失血性休克和复苏（HS/R）模型的短期存活率。 然而，HS/R 中 H2 的潜在分子机制尚不清楚。 内皮糖萼（EG）损伤导致与 HS/R 相关的血液动力学衰竭。 在这项研究中，我们检验了这样一个假设，即 H2 通过抑制黄嘌呤氧化还原酶（XOR）和/或防止肿瘤坏死因子-α（TNF-α）介导的硫酸乙酰肝素聚糖-1（syndecan-1）脱落来减轻氧化应激EG 损伤。
通过将平均动脉压（MAP）降低至 35mmHg 60分钟来诱导 HS/R，然后进行复苏。 在休克后，大鼠分别在存在或不存在 XOR 抑制剂（XOR-I）的情况下，吸入氧气或 H2 +氧气。 在第二个测试中，大鼠仅接受氧气或抗肿瘤坏死因子（TNF）-α单克隆抗体与氧气或 H2。 复苏后 2 小时，测量 XOR 活性、嘌呤代谢物、细胞因子和硫酸乙酰肝素聚糖-1，并在复苏后 6 小时评估存活率。
H2 和 XOR-I 均抑制 MAP 降低并提高存活率。 H2 不影响 XOR 活性，并且 XOR-I 和 H2 的治疗效果具有加性。 H2 抑制血浆 TNF-α和硫酸乙酰肝素聚糖-1表达； 然而，在存在抗 TNF-α单克隆抗体的情况下，未观察到 H2 的额外治疗效果。
休克后吸入 H2 可稳定 HS/R 模型中的血液动力学并提高存活率，而与 XOR 无关。 H2 的治疗作用部分是通过抑制 TNF-α依赖性硫酸乙酰肝素聚糖-1脱落介导的。
