TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury.
TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury.
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TLR4作为HMGB1介导的肝缺血/再灌注损伤后急性肺损伤的受体
DOI：
10.1038/labinvest.2013.66
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Yang Z;Deng Y;Su D;Tian J;Gao Y;He Z;Wang X
急性肺损伤（ALI）常发生于肝移植及肝脏大手术后。肝脏缺血/再灌注（I/R）损伤后受损肝脏释放的促炎介质可能导致这种类型的ALI，但其潜在机制尚未完全明确。高迁移率族蛋白B1（HMGB1）是一种新近发现的促炎细胞因子，研究发现肝脏I/R损伤后血清中HMGB1水平显著升高。本研究旨在探讨HMGB1是否作为刺激因子参与其中，以及其下游的Toll样受体4（TLR4）、p38丝裂原活化蛋白激酶（p38MAPK）和激活蛋白-1（AP-1）信号通路是否在肝脏I/R损伤诱导的ALI发生发展中起介导作用。在大鼠肝脏I/R损伤模型中诱导出广泛的ALI和肺部炎症。肝脏I/R损伤后血清HMGB1水平显著升高，更重要的是，肺组织中HMGB1 mRNA和蛋白的表达也显著增加。我们进一步发现，肝脏I/R损伤增强了肺组织中TLR4 mRNA和蛋白的表达，以及p38MAPK和AP-1的活性。通过用表达靶向TLR4基因的小发夹RNA的pGCSIL - GFP慢病毒（TLR4 - shRNA慢病毒）感染来抑制肺组织中TLR4的表达，可显著减轻ALI、肺部炎症以及肺组织中p38MAPK和AP - 1的活性。这些研究结果表明，HMGB1可能参与了肝脏I/R损伤诱导ALI的潜在机制，且其下游的TLR4、p38MAPK和AP - 1信号通路在ALI的发生发展中可能是重要的介导因素。
Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injury-induced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.
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影响因子：
15.9
作者：
Andonegui, G;Bonder, CS;Kubes, P
通讯作者：
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