期刊
SHOCK
卷 33, 期 1, 页码 31-42出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0b013e3181c02c1f
关键词
Apoptosis; dihydrosphingosine-1-phosphate; inflammation; kidney; liver; necrosis; sphingolipid; sphingosine-1-phosphate
资金
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK058547] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM067081] Funding Source: NIH RePORTER
- NIDDK NIH HHS [R01 DK-58547, R01 DK058547] Funding Source: Medline
- NIGMS NIH HHS [R01 GM-067081, R01 GM067081-06, R01 GM067081] Funding Source: Medline
Hepatic ischemia/reperfusion (I/R) injury is a major complication after liver transplantation, major hepatic resection, or prolonged portal vein occlusion. Furthermore, acute kidney injury is frequent after hepatic I/R and greatly increases postoperative complications. Sphinganine-1-phosphate is a sphingolipid with uncharacterized physiological effects. We serendipitously determined that plasma levels of sphinganine-1-phosphate fell significantly after liver I/R in mice. In this study, we hypothesized that repletion of plasma sphinganine-1-phosphate would protect against liver and kidney injuries after liver I/R. C57BL/6 mice were subjected to 60 min of partial hepatic I/R and treated with either vehicle or with sphinganine-1-phosphate (given immediately before and 2 h after reperfusion). Vehicle-treated mice subjected to liver I/R developed acute liver and kidney injuries with elevated plasma alanine aminotransferase and creatinine 5 and 24 h after liver I/R. However, liver and kidney injuries were significantly attenuated with sphinganine-1-phosphate treatment. Sphinganine-1-phosphate markedly inhibited liver and kidney necrosis and apoptosis 24 h after liver I/R. Moreover, sphinganine-1-phosphate attenuated neutrophil infiltration, reduced plasma IL-6 and TNF-alpha upregulation, and preserved liver and kidney vascular integrity while reducing liver and kidney F-actin degradation after liver I/R. Finally, sphinganine-1-phosphate-mediated hepatic and renal protection was blocked by VPC23019, an antagonist for sphingosine-1-phosphate type 1 receptor. Therefore, sphinganine-1-phosphate improves acute liver and kidney injuries after hepatic I/R via sphingosine-1-phosphate type 1 receptor-mediated inhibition of necrosis and apoptosis and by improving vascular integrity. Harnessing the mechanisms of cytoprotection with sphinganine-1-phosphate activation may lead to new therapies for perioperative hepatic I/R injury and subsequent remote organ injury.
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