Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury.
Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury.
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DOI：
10.1016/j.redox.2014.01.013
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发表时间：
2014
期刊：
影响因子：
11.4
通讯作者：
Mantell LL
中科院分区：
文献类型：
--
作者：
Entezari M;Javdan M;Antoine DJ;Morrow DM;Sitapara RA;Patel V;Wang M;Sharma L;Gorasiya S;Zur M;Wu W;Li J;Yang H;Ashby CR;Thomas D;Wang H;Mantell LL
长时间暴露于高氧导致急性肺损伤（ALI），伴随着肺中促炎细胞因子和白细胞浸润水平的显著升高。然而，高氧诱导的促炎性ALI的机制仍有待阐明。在这项研究中，我们使用成年小鼠模型研究了促炎症细胞因子高迁移率族蛋白1（HMGB 1）在高氧炎症性肺损伤中的作用。C57 BL/6小鼠暴露于≥ 99%O2（高氧）显著增加了严重炎性肺损伤发生前支气管肺泡灌洗液（BALF）中HMGB 1的蓄积。在高氧小鼠气道中，HMGB 1被高度乙酰化，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，肠内施用重组HMGB 1（rHMGB 1）引起白细胞浸润到肺中的显著增加。中和抗HMGB 1抗体，高氧前管理显着减弱肺水肿和炎症反应，如减少总蛋白含量，湿/干重比，和白细胞在气道中的数量。当在高氧暴露开始后给予HMGB 1抑制剂时，也观察到这种保护作用。脂肪族抗氧化剂丙酮酸乙酯（EP）可抑制高氧巨噬细胞分泌HMGB 1，减轻高氧肺损伤。总的来说，我们的数据表明，HMGB 1在介导高氧ALI中起着关键作用，通过招募白细胞进入肺部。如果这些结果可以转化为人类，它们表明HMGB 1抑制剂为通过机械通气接受高氧的患者提供了氧化性炎症性肺损伤的治疗方案。暴露于高氧导致高水平的气道HMGB 1的积累，其先于炎性急性肺损伤（ALI）。气道HMGB 1通过募集包括中性粒细胞在内的白细胞在介导高氧诱导的炎性ALI中起关键作用。细胞外积累的HMGB 1-在长时间暴露于高氧时被过度乙酰化，以不同的氧化还原状态存在。即使在高氧暴露开始后给予小分子EP，也可以通过抑制HMGB 1释放到细胞外环境中来减轻高氧诱导的炎性ALI。
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. Exposure to hyperoxia results in accumulation of high levels of airway HMGB1 that precede inflammatory acute lung injury (ALI). Airway HMGB1 is critical in mediating hyperoxia-induced inflammatory ALI via recruiting leukocytes including neutrophils. Extracellular HMGB1-accumulated upon prolonged exposure to hyperoxia is hyperacetylated, existing in different redox states. Small molecule EP, administrated even after the onset of hyperoxic exposure, can mitigate hyperoxia-induced inflammatory ALI by inhibiting HMGB1 release into the extracellular milieu.
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影响因子：
25.7
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
7.4
作者：
Franek, WR;Morrow, DMP;Mantell, UL
通讯作者：
Mantell, UL
影响因子：
4.8
作者：
Franek, WR;Horowitz, S;Mantell, LL
通讯作者：
Mantell, LL
DOI：
10.1152/ajplung.00037.2001
发表时间：
2002-07-01
影响因子：
4.9
作者：
Mantell, LL;Shaffer, TH;Davis, JM
通讯作者：
Davis, JM
影响因子：
12.4
作者：
Mantell, LL;Kazzaz, JA;Horowitz, S
通讯作者：
Horowitz, S