title: TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury.
abstract: 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.
authors: Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Zhongwei
authors: Z
authors: Yang
authors: Yuxiao
authors: Y
authors: Deng
authors: Diansan
authors: D
authors: Su
authors: Jie
authors: J
authors: Tian
authors: Yuan
authors: Y
authors: Gao
authors: Zhengyu
authors: Z
authors: He
authors: Xiangrui
authors: X
authors: Wang
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D024243:HMGB1 Protein / Q000097:blood*; D008099:Liver / Q000098:blood supply*; D008168:Lung / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases
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