Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, People's Republic of China.
Shock. 2012 May;37(5):548-55. doi: 10.1097/SHK.0b013e31824ddc81.
Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Recently, our and other studies have found that hydrogen gas (H₂) treatment can ameliorate the lung injury induced by sepsis, ventilator, hyperoxia, and ischemia-reperfusion. However, the molecular mechanisms by which H₂ ameliorates lung injury remain unclear. In the current study, we investigated whether H₂ or hydrogen-rich saline (HS) could exert protective effects in a mouse model of ALI induced by intratracheal administration of lipopolysaccharide (LPS) via inhibiting the nuclear factor κB (NF-κB) signaling pathway-mediated inflammation and apoptosis. Two percent of H₂ was inhaled for 1 h beginning at 1 and 6 h after LPS administration, respectively. We found that LPS-challenged mice exhibited significant lung injury characterized by the deterioration of histopathology and histologic scores, wet-to-dry weight ratio, and oxygenation index (PaO₂/FIO₂), as well as total protein in the bronchoalveolar lavage fluid (BALF), which was attenuated by H₂ treatment. Hydrogen gas treatment inhibited LPS-induced pulmonary early and late NF-κB activation. Moreover, H₂ treatment dramatically prevented the LPS-induced pulmonary cell apoptosis in LPS-challenged mice, as reflected by the decrease in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) staining-positive cells and caspase 3 activity. Furthermore, H₂ treatment markedly attenuated LPS-induced lung neutrophil recruitment and inflammation, as evidenced by downregulation of lung myeloperoxidase activity, total cells, and polymorphonuclear neutrophils in BALF, as well as proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, interleukin 6, and high-mobility group box 1) and chemokines (keratinocyte-derived chemokine, macrophage inflammatory protein [MIP] 1α, MIP-2, and monocyte chemoattractant protein 1) in BALF. In addition, i.p. injection of 10 mL/kg hydrogen-rich saline also significantly attenuated the LPS-induced ALI. Collectively, these results demonstrate that molecular hydrogen treatment ameliorates LPS-induced ALI through reducing lung inflammation and apoptosis, which may be associated with the decreased NF-κB activity. Hydrogen gas may be useful as a novel therapy to treat ALI. munosorbent assay; H₂-hydrogen gas; HMGB1-high-mobility group box 1; HS-hydrogen-rich saline; i.t.-intratracheal; KC-keratinocyte-derived chemokine; LPS-lipopolysaccharide; MCP-1-monocyte chemoattractant protein 1; MIP-1α-macrophage inflammatory protein 1α; MIP-2-macrophage inflammatory protein 2; MPO-myeloperoxidase; PBS-phosphate-buffered saline; PMNs-polymorphonuclear neutrophils; TUNEL-deoxynucleotidyl transferase dUTP nick end labeling; W/D-wet-to-dry.
急性肺损伤（ALI）仍然是危重病患者发病率和死亡率的主要原因。最近，我们和其他研究发现，氢气（H₂）治疗可以改善脓毒症、呼吸机、高氧和缺血再灌注引起的肺损伤。然而，H₂改善肺损伤的分子机制尚不清楚。在本研究中，我们通过抑制核因子 κB（NF-κB）信号通路介导的炎症和细胞凋亡，研究了 H₂或富氢盐水（HS）是否可以在脂多糖（LPS）经气管内给药诱导的小鼠 ALI 模型中发挥保护作用。LPS 给药后 1 h 和 6 h 分别开始吸入 2%的 H₂1 h。我们发现，LPS 攻击的小鼠表现出明显的肺损伤，其特征是组织病理学和组织学评分、湿重/干重比和氧合指数（PaO₂/FIO₂）恶化，以及支气管肺泡灌洗液（BALF）中的总蛋白增加，H₂ 治疗可减轻这种损伤。H₂ 治疗抑制了 LPS 诱导的肺早期和晚期 NF-κB 激活。此外，H₂ 治疗显著防止了 LPS 诱导的 LPS 攻击小鼠的肺细胞凋亡，这反映在 TUNEL（脱氧核苷酸转移酶 dUTP 缺口末端标记）染色阳性细胞和 caspase 3 活性减少。此外，H₂ 治疗显著下调了肺髓过氧化物酶活性、BALF 中的总细胞和多形核粒细胞以及促炎细胞因子（肿瘤坏死因子-α、白细胞介素 1β、白细胞介素 6 和高迁移率族蛋白 1）和趋化因子（角质形成细胞衍生的趋化因子、巨噬细胞炎性蛋白 [MIP] 1α、MIP-2 和单核细胞趋化蛋白 1），从而减轻了 LPS 诱导的肺中性粒细胞募集和炎症。此外，腹腔注射 10 mL/kg 富氢盐水也显著减轻了 LPS 诱导的 ALI。总之，这些结果表明，分子氢治疗通过减少肺炎症和细胞凋亡来改善 LPS 诱导的 ALI，这可能与 NF-κB 活性降低有关。氢气可能是治疗 ALI 的一种有用的新疗法。酶联免疫吸附试验；H₂-氢气；HMGB1-高迁移率族蛋白 1；HS-富氢盐水；i.t.-气管内；KC-角质形成细胞衍生的趋化因子；LPS-脂多糖；MCP-1-单核细胞趋化蛋白 1；MIP-1α-巨噬细胞炎性蛋白 1α；MIP-2-巨噬细胞炎性蛋白 2；MPO-髓过氧化物酶；PBS-磷酸盐缓冲盐水；PMN-多形核粒细胞；TUNEL-脱氧核苷酸转移酶 dUTP 缺口末端标记；W/D-湿重/干重。
