Li Yuehua, Xiang Meng, Yuan Youzhong, Xiao Guozhi, Zhang Jian, Jiang Yong, Vodovotz Yoram, Billiar Timothy R, Wilson Mark A, Fan Jie
Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Physiol Regul Integr Comp Physiol. 2009 Dec;297(6):R1670-80. doi: 10.1152/ajpregu.00445.2009. Epub 2009 Oct 14.
Hemorrhagic shock (HS) due to major trauma predisposes the host to the development of acute lung inflammation and injury. The lung vascular endothelium is an active organ that plays a central role in the development of acute lung injury through generating reactive oxygen species and synthesizing and releasing of a number of inflammatory mediators, including leukocyte adhesion molecules that regulate neutrophils emigration. Previous study from our laboratory has demonstrated that in a setting of sepsis, toll-like receptor-4 (TLR4) signaling can induce TLR2 expression in endothelial cells (ECs), thereby increasing the cells' response to TLR2 ligands. The present study tested the hypothesis that TLR4 activation by HS and the resultant increased TLR2 surface expression in ECs might contribute to the mechanism underlying HS-augmented activation of lung ECs. The results show that high-mobility group box 1 (HMGB1) through TLR4 signaling mediates HS-induced surface expression of TLR2 in the lung and mouse lung vascular endothelial cells (MLVECs). Furthermore, the results demonstrate that HMGB1 induces activation of NAD(P)H oxidase and expression of ICAM-1 in the lung, and MLVECs sequentially depend on TLR4 in the early phase and on TLR2 in the late phase following HS. Finally, the data indicate an important role of the increased TLR2 surface expression in enhancing the activation of MLVECs and augmenting pulmonary neutrophil infiltration in response to TLR2 agonist peptidoglycan. Thus, induction of TLR2 surface expression in lung ECs, induced by HS and mediated by HMGB1/TLR4 signaling, is an important mechanism responsible for endothelial cell-mediated inflammation and organ injury following trauma and hemorrhage.
严重创伤导致的失血性休克（HS）使宿主易发生急性肺炎症和损伤。肺血管内皮是一个活跃的器官，通过产生活性氧以及合成和释放多种炎症介质，包括调节中性粒细胞迁移的白细胞黏附分子，在急性肺损伤的发生发展中起核心作用。我们实验室之前的研究表明，在脓毒症情况下，Toll样受体4（TLR4）信号传导可诱导内皮细胞（ECs）中TLR2表达，从而增强细胞对TLR2配体的反应。本研究检验了以下假设：HS激活TLR4以及由此导致的ECs中TLR2表面表达增加可能促成HS增强肺ECs激活的潜在机制。结果显示，高迁移率族蛋白B1（HMGB1）通过TLR4信号传导介导HS诱导的肺和小鼠肺血管内皮细胞（MLVECs）中TLR2的表面表达。此外，结果表明HMGB1诱导肺中NAD（P）H氧化酶的激活和细胞间黏附分子-1（ICAM-1）的表达，并且MLVECs在HS后的早期阶段依次依赖TLR4，在后期依赖TLR2。最后，数据表明TLR2表面表达增加在增强MLVECs激活以及增强对TLR2激动剂肽聚糖的肺中性粒细胞浸润方面具有重要作用。因此，HS诱导并由HMGB1/TLR4信号传导介导的肺ECs中TLR2表面表达的诱导是创伤和出血后内皮细胞介导的炎症和器官损伤的重要机制。
