长时间暴露于高氧会导致急性肺损伤(ALI),伴随着促炎细胞因子水平的显着升高和肺部白细胞浸润。然而,高氧诱导的促炎性ALI的潜在机制仍有待阐明.在这项研究中,我们研究了促炎细胞因子高迁移率族蛋白1(HMGB1)在高氧性炎性肺损伤中的作用,使用成年小鼠模型。C57BL/6小鼠暴露于≥99%O2(高氧)显着增加了严重炎性肺损伤发作之前支气管肺泡灌洗液(BALF)中HMGB1的积累。在高氧小鼠的气道中,HMGB1是高乙酰化的,并以各种氧化还原形式存在。与用非特异性肽处理的动物相比,气管内施用重组HMGB1(rHMGB1)导致白细胞浸润到肺中的显著增加。中和抗HMGB1抗体,在高氧前给药可显着减轻肺水肿和炎症反应,如总蛋白质含量下降所示,湿/干重比,以及气道中白细胞的数量。当在高氧暴露开始后施用HMGB1抑制剂时,也观察到这种保护。脂肪族抗氧化剂,丙酮酸乙酯(EP),抑制高氧巨噬细胞分泌HMGB1,减轻高氧肺损伤。总的来说,我们的数据表明,HMGB1通过将白细胞募集到肺部,在介导高氧ALI中起关键作用.如果这些结果可以转化为人类,他们建议,HMGB1抑制剂为通过机械通气接受高氧治疗的患者提供氧化性炎症性肺损伤的治疗方案.
Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.