HMGB1 contributes to the development of acute lung injury after hemorrhage
HMGB1 contributes to the development of acute lung injury after hemorrhage
复制标题
DOI：
10.1152/ajplung.00359.2004
复制
发表时间：
2005-05-01
影响因子：
4.9
通讯作者：
Abraham, E
中科院分区：
文献类型：
--
作者：
Kim, JY;Park, JS;Abraham, E
高迁移率族蛋白 1 (HMGB1) 是一种新型炎症反应晚期介质，可导致内毒素诱导的急性肺损伤和脓毒症相关的死亡。尽管急性肺损伤是严重失血的常见并发症，但 HMGB1 在这种情况下对器官系统功能障碍的影响尚未得到研究。在本研究中，在基线条件下在肺内皮细胞和巨噬细胞中检测到 HMGB1。出血后，除了内皮细胞和巨噬细胞呈阳性染色外，肺部还存在表达 HMGB1 的中性粒细胞。研究发现，肺中 HMGB1 的表达在出血后 4 小时内增加，并在失血后 72 小时以上保持升高状态。中性粒细胞似乎有助于出血后肺 HMGB1 表达的增加，因为在用环磷酰胺使中性粒细胞减少的小鼠出血后，没有发现肺 HMGB1 水平发生变化。出血后 HMGB1 的血浆浓度也增加。通过施用抗 HMGB1 抗体阻断 HMGB1，可防止出血引起的肺部 NF-κ B 核转位和肺部促炎细胞因子水平的增加，包括角质形成细胞衍生的趋化因子、IL-6 和 IL-1 β。同样，当出血后注射抗 HMGB1 抗体时，肺部中性粒细胞的积累以及增强的肺通透性都会减少。这些结果表明，出血导致肺部 HMGB1 表达增加，主要通过中性粒细胞来源，并且 HMGB1 参与出血引起的急性肺损伤。
High mobility group box 1 (HMGB1) is a novel late mediator of inflammatory responses that contributes to endotoxin-induced acute lung injury and sepsis-associated lethality. Although acute lung injury is a frequent complication of severe blood loss, the contribution of HMGB1 to organ system dysfunction in this setting has not been investigated. In this study, HMGB1 was detected in pulmonary endothelial cells and macrophages under baseline conditions. After hemorrhage, in addition to positively staining endothelial cells and macrophages, neutrophils expressing HMGB1 were present in the lungs. HMGB1 expression in the lung was found to be increased within 4 h of hemorrhage and then remained elevated for more than 72 h after blood loss. Neutrophils appeared to contribute to the increase in posthemorrhage pulmonary HMGB1 expression since no change in lung HMGB1 levels was found after hemorrhage in mice made neutropenic with cyclophosphamide. Plasma concentrations of HMGB1 also increased after hemorrhage. Blockade of HMGB1 by administration of anti-HMGB1 antibodies prevented hemorrhage-induced increases in nuclear translocation of NF-kappa B in the lungs and pulmonary levels of proinflammatory cytokines, including keratinocyte-derived chemokine, IL-6, and IL-1 beta. Similarly, both the accumulation of neutrophils in the lung as well as enhanced lung permeability were reduced when anti-HMGB1 antibodies were injected after hemorrhage. These results demonstrate that hemorrhage results in increased HMGB1 expression in the lungs, primarily through neutrophil sources, and that HMGB1 participates in hemorrhage-induced acute lung injury.