Hepatic Stellate Cells Promote Hepatocyte Engraftment in Rat Liver After Prostaglandin-Endoperoxide Synthase Inhibition
Hepatic Stellate Cells Promote Hepatocyte Engraftment in Rat Liver After Prostaglandin-Endoperoxide Synthase Inhibition
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DOI：
10.1053/j.gastro.2009.03.003
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发表时间：
2009-06-01
期刊：
影响因子：
29.4
通讯作者：
Gupta, Sanjeev
中科院分区：
文献类型：
--
作者：
Enami, Yuta;Bandi, Sriram;Gupta, Sanjeev
背景和目标：肝脏炎症在细胞移植到肝脏后立即发生，但这一过程的机制尚未完全确定。我们研究了肝细胞移植后通过合成前列腺素、前列环素、血栓烷和其他前列腺素介导肝脏炎症的环氧合酶途径。方法：将F344大鼠肝细胞移植到同系二肽基肽酶IV缺陷的F344大鼠体内。分析了环氧合酶途径的变化，并初步阻断了特定途径;测定了对细胞植入和天然肝细胞的影响。结果如下：肝细胞移植诱导了前列腺素内过氧化物酶1和2的肝表达，其催化前列腺素H2的产生，以及下游因子血栓烷合酶，其产生血栓烷A2（炎症中血管和血小板反应的调节剂）。移植的肝细胞与表达胰高血糖素-内过氧化物酶的肝细胞接近。移植前给予那普利生或塞来昔布的大鼠移植肝细胞数量增加，但给予呋替格雷（一种血栓烷合酶抑制剂）或氯泊格雷（一种抗血小板药物）的大鼠移植肝细胞数量没有增加。纳曲林和塞来昔布不能预防肝缺血或中性粒细胞、枯否细胞或炎性细胞因子的活化，但它们确实诱导肝星状细胞表达细胞保护基因、血管内皮生长因子和肝细胞生长因子、基质型金属蛋白酶和金属蛋白酶组织抑制剂-1，这些基因调节肝重塑。结论：环氧合酶通路的激活干扰了肝细胞移植在肝脏中的植入。药理学阻断野牡丹素-内过氧化物酶刺激肝星状细胞和改善细胞植入。
Background & Aims: Hepatic inflammation occurs immediately after cells are transplanted to the liver, but the mechanisms that underlie this process are not fully defined. We examined cyclooxygenase pathways that mediate hepatic inflammation through synthesis of prostaglandins, prostacyclins, thromboxanes, and other prostanoids following transplantation of hepatocytes. Methods: We transplanted F344 rat hepatocytes into syngeneic dipeptidyl peptidase IV-deficient F344 rats. Changes in cyclooxygenase pathways were analyzed, and specific pathways were blocked pharmacologically; the effects on cell engraftment and native liver cells were determined. Results: Transplantation of hepatocytes induced hepatic expression of prostaglandin-endoperoxide synthases 1 and 2, which catalyze production of prostaglandin H2, as well as the downstream factor thromboxane synthase, which produces thromboxane A2 (a regulator of vascular and platelet responses in inflammation). Transplanted hepatocytes were in proximity with liver cells that expressed prostaglandin-endoperoxide synthases. The number of engrafted hepatocytes increased in rats given naproxen or celecoxib before transplantation but not in rats given furegrelate (an inhibitor of thromboxane synthase) or clopodigrel (an antiplatelet drug). Naproxen and celecoxib did not prevent hepatic ischemia or activation of neutrophils, Kupffer cells, or inflammatory cytokines, but they did induce hepatic stellate cells to express cytoprotective genes, vascular endothelial growth factor and hepatocyte growth factor, and matrix-type metalloproteinases and tissue inhibitor of metalloproteinase-1, which regulate hepatic remodeling. Conclusions: Activation of cyclooxygenase pathways interferes with engraftment of transplanted hepatocytes in the liver. Pharmacologic blockade of prostaglandin-endoperoxide synthases stimulated hepatic stellate cells and improved cell engraftment.