Toll-like receptor 4 mediates acute lung injury induced by high mobility group box-1.
Toll-like receptor 4 mediates acute lung injury induced by high mobility group box-1.
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Toll 样受体 4 介导高迁移率族 box-1 诱导的急性肺损伤。
DOI：
10.1371/journal.pone.0064375
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Deng Y;Yang Z;Gao Y;Xu H;Zheng B;Jiang M;Xu J;He Z;Wang X
急性肺损伤（ALI）被认为是危重症患者呼吸衰竭的主要原因。临床研究发现，在脓毒症患者及出血后的患者中，循环中高迁移率族蛋白B1（HMGB - 1）水平升高与ALI密切相关，但潜在机制尚不清楚。细胞外的HMGB - 1具有类似细胞因子的特性，可与Toll样受体4（TLR4）结合，据报道TLR4在ALI的发病机制中发挥重要作用。本研究旨在确定HMGB - 1是否直接导致ALI，以及TLR4信号通路是否参与这一过程。
使用重组人HMGB - 1（rhHMGB - 1）诱导雄性Sprague - Dawley大鼠发生ALI。在给予HMGB - 1处理2小时后收集肺标本。评估肺组织中肿瘤坏死因子 - α（TNF - α）、白细胞介素 - 1β（IL - 1β）、TLR4蛋白及TLR4信使核糖核酸（mRNA）的水平，以及肺组织的病理变化。在细胞研究中，给予rhHMGB - 1处理24小时后收集肺泡巨噬细胞系NR8383，检测培养基中TNF - α和IL - 1β的水平，以及细胞中TLR4蛋白和mRNA的水平。使用TLR4 - 短发夹核糖核酸（shRNA）慢病毒抑制TLR4表达，并使用中和性抗HMGB1抗体在体外和体内中和rhHMGB - 1。
在接受rhHMGB - 1处理的动物肺中发现了肺损伤特征，且IL - 1β和TNF - α水平显著升高。经rhHMGB - 1处理后，培养的NR8383细胞被激活，导致IL - 1β和TNF - α释放。rhHMGB - 1可使TLR4表达大幅上调。使用特异性抗体抑制TLR4或中和HMGB1，在体内和体外均减弱了由HMGB - 1诱导的炎症反应。
HMGB - 1可激活肺泡巨噬细胞产生促炎细胞因子，并通过依赖TLR - 4的机制诱导ALI。
Acute lung injury (ALI) is considered to be the major cause of respiratory failure in critically ill patients. Clinical studies have found that in patients with sepsis and after hemorrhage, the elevated level of high mobility group box-1(HMGB-1) in their circulation is highly associated with ALI, but the underlying mechanism remains unclear. Extracellular HMGB-1 has cytokine-like properties and can bind to Toll-like Receptor-4 (TLR4), which was reported to play an important role in the pathogenesis of ALI. The aim of this study was to determine whether HMGB-1 directly contributes to ALI and whether TLR4 signaling pathway is involved in this process. Recombinant human HMGB-1 (rhHMGB-1) was used to induce ALI in male Sprague-Dawley rats. Lung specimens were collected 2 h after HMGB-1 treatment. The levels of TNF-α, IL-1β, TLR4 protein, and TLR4 mRNA in lungs as well as pathological changes of lung tissue were assessed. In cell studies, the alveolar macrophage cell line, NR8383, was collected 24 h after rhHMGB-1 treatment and the levels of TNF-α and IL-1β in cultured medium as well as TLR4 protein and mRNA levels in the cell were examined. TLR4-shRNA-lentivirus was used to inhibit TLR4 expression, and a neutralizing anti-HMGB1 antibody was used to neutralize rhHMGB-1 both in vitro and in vivo. Features of lung injury and significant elevation of IL-1β and TNF-α levels were found in lungs of rhHMGB-1-treated animals. Cultured NR8383 cells were activated by rhHMGB-1 treatment and resulted in the release of IL-1β and TNF-α. TLR4 expression was greatly up-regulated by rhHMGB-1. Inhibition of TLR4 or neutralization of HMGB1 with a specific antibody also attenuated the inflammatory response induced by HMGB-1 both in vivo and in vitro. HMGB-1 can activate alveolar macrophages to produce proinflammatory cytokines and induce ALI through a mechanism that relies on TLR-4.
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影响因子：
5.5
作者：
Park, JS;Gamboni-Robertson, F;Abraham, E
通讯作者：
Abraham, E
影响因子：
6.7
作者：
Hatada, T;Wada, H;Maruyama, I
通讯作者：
Maruyama, I
影响因子：
2.2
作者：
Li, JH;Wang, HC;Yang, H
通讯作者：
Yang, H
DOI：
10.1152/ajplung.00359.2004
发表时间：
2005-05-01
影响因子：
4.9
作者：
Kim, JY;Park, JS;Abraham, E
通讯作者：
Abraham, E
Toll样受体4介导内毒素和过度充气诱导的中性粒细胞固次和肺损伤。
影响因子：
8.8
作者：
Hu G;Malik AB;Minshall RD
通讯作者：
Minshall RD