Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Lab Invest. 2013 Jul;93(7):792-800. doi: 10.1038/labinvest.2013.66. Epub 2013 Apr 29.
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.
急性肺损伤（ALI）在肝移植和大肝手术后经常发生。肝缺血/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形式的 ALI，但潜在机制尚未得到很好的描述。高迁移率族蛋白 1（HMGB1）是最近发现的一种促炎细胞因子，在肝 I / R 损伤后血清中发现其含量明显升高。本研究探讨了 HMGB1 是否作为刺激因子参与，其下游 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）信号通路是否作为肝 I / R 损伤诱导的 ALI 发展的介质。在肝 I / R 损伤的大鼠模型中诱导广泛的 ALI 和肺炎症。肝 I / R 损伤后血清 HMGB1 明显升高，更重要的是，肺组织中 HMGB1 mRNA 和蛋白的表达也明显增加。我们进一步发现肝 I / R 损伤增强了 TLR4 mRNA 和蛋白的表达，以及肺组织中 p38MAPK 和 AP-1 的活性。通过感染 pGCSIL-GFP-短发夹 RNA 慢病毒表达靶向 TLR4 基因的短发夹 RNA（TLR4-shRNA 慢病毒）抑制肺组织中的 TLR4 表达，明显减轻了 ALI、肺炎症和肺组织中 p38MAPK 和 AP-1 的活性。这些发现表明 HMGB1 可能有助于肝 I / R 损伤诱导的 ALI 的潜在机制，其下游 TLR4、p38MAPK 和 AP-1 信号通路可能是 ALI 发展的重要介质。
