Endothelin-1 receptor A blocker darusentan decreases hepatic changes and improves liver repopulation after cell transplantation in rats.
Endothelin-1 receptor A blocker darusentan decreases hepatic changes and improves liver repopulation after cell transplantation in rats.
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DOI：
10.1002/hep.26766
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发表时间：
2014-03
期刊：
影响因子：
13.5
通讯作者：
Gupta, Sanjeev
中科院分区：
文献类型：
--
作者：
Bahde, Ralf;Kapoor, Sorabh;Viswanathan, Preeti;Spiegel, Hans-Ullrich;Gupta, Sanjeev
细胞移植引起的肝脏缺血和血管收缩因子，如内皮素-1的募集，导致移植细胞的清除，并给肝脏再生带来问题。因此，我们确定了有效阻断内皮素-1受体A型的达鲁生坦是否有利于细胞植入。我们将含或不含达鲁生坦的F344大鼠原代肝细胞移植到二肽基肽酶IV缺陷大鼠体内。微循环事件的分析包括肝脏缺血、内皮损伤，包括基因表达阵列，以及库普弗细胞、中性粒细胞或肝星状细胞的激活。采用逆皮质醇-部分肝切除模型进行肝脏回流研究。在培养的大鼠肝细胞和CFSC-8B大鼠肝星状细胞上检测达鲁生坦是否具有直接细胞保护作用。我们发现达鲁生坦可引起肝窦血管扩张，使更多的移植细胞沉积在肝实质内，减轻肝脏缺血和内皮损伤。这减少了内皮生物基因表达的扰动，包括血管张力、炎症、细胞黏附或细胞损伤的调节，而不是药物治疗的对照组。此外，在达鲁生坦治疗的动物中，细胞移植诱导的Kupffer细胞的激活，尽管不是中性粒细胞，但减少了，更少的肝星状细胞表达结蛋白。在接受达洛森坦治疗的大鼠中，与未接受药物治疗的对照组相比，细胞植入的改善导致了更大程度的肝脏再生。在细胞培养实验中，达鲁生坦不能刺激肝星状细胞释放细胞保护因子，如血管内皮生长因子。此外，达鲁生坦不能保护肝细胞免受肿瘤坏死因子-α或氧化应激诱导的毒性。体外阻断内皮素A受体并不能改善随后移植的肝细胞的植入。我们的结论是，全身应用达鲁生坦可减少肝脏缺血相关事件，从而间接改善细胞植入和肝脏再生长。这种血管机制将允许开发以药物为基础的组合方案，以帮助优化细胞治疗。
Cell transplantation-induced hepatic ischemia and recruitment of vasoconstrictors, e.g., endothelin-1, leads to clearance of transplanted cells and poses problems for liver repopulation. Therefore, we determined whether darusentan, which potently blocks endothelin-1 receptor type A, could benefit cell engraftment. We transplanted primary F344 rat hepatocytes with or without darusentan in dipeptidyl peptidase IV-deficient rats. Analysis of microcirculatory events included hepatic ischemia, endothelial injury, including with gene expression arrays, and activations of Kupffer cells, neutrophils or hepatic stellate cells. The retrorsine-partial hepatectomy model was used for liver repopulation studies. Whether darusentan was directly cytoprotective was examined in cultured rat hepatocytes or CFSC-8B rat hepatic stellate cells. We found darusentan induced hepatic sinusoidal vasodilation, caused more transplanted cells to be deposited in liver parenchyma, and decreased hepatic ischemia and endothelial injury. This lessened perturbations in expression of endothelial biology genes, including regulators of vessel tone, inflammation, cell adhesion, or cell damage versus drug-untreated controls. Moreover, in darusentan-treated animals, cell transplantation-induced activation of Kupffer cells, albeit not of neutrophils, decreased, and fewer hepatic stellate cells expressed desmin. In darusentan-treated rats, improvements in cell engraftment led to greater extent of liver repopulation compared with drug-untreated controls. In cell culture assays, darusentan did not stimulate release of cytoprotective factors, such as vascular endothelial growth factor, from hepatic stellate cells. Moreover, darusentan did not protect hepatocytes from TNF-α- or oxidative stress-induced toxicity. Endothelin receptor A blockade in vitro did not improve engraftment of subsequently transplanted hepatocytes. We concluded that systemic administration of darusentan decreased hepatic ischemia-related events and thus indirectly improved cell engraftment and liver repopulation. This vascular mechanism will permit development of combinatorial drug-based regimens to help optimize cell therapy.
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