Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain.
Am J Physiol Gastrointest Liver Physiol. 2018 Sep 1;315(3):G399-G407. doi: 10.1152/ajpgi.00112.2018. Epub 2018 Jun 21.
Intrahepatic cholestasis of pregnancy (ICP) is frequently accompanied by pruritus, whose etiology has been associated with an enhanced production of lysophosphatidic acid (LPA) by the combined action of phospholipase A1/A2 (PLA1/PLA2) and autotaxin (ATX). Here, we have investigated whether the placenta is involved in LPA release to maternal circulation during ICP. Serum levels of ATX and LPA (determined by ELISA) were elevated in women with ICP, and a correlation between both parameters was found. No relationship between serum levels of ATX or LPA and bile acids was found. Expression levels of ATX and PLA2 were determined by RT-qPCR and Western blot. Placenta ATX but not PLA2 was significantly upregulated in ICP, and a tendency to increase was found at the protein level. A correlation between serum ATX and placental ATX mRNA levels was found. In human placenta at term, ATX was clearly detected (by immunofluorescence) in Hofbauer cells, but only faintly in trophoblast cells. In pregnant rats, the expression of Atx and Pla2 in placenta was lower than in liver. When obstructive cholestasis was imposed by bile duct ligation from day 14 of gestation until term, placenta Atx and Pla2 expression was markedly enhanced, and overexpression was confirmed at the protein level for Pla2, whereas Atx protein was not detected. In conclusion, the placenta substantially participates in LPA production during gestation. This contribution is markedly higher during maternal cholestasis and hence, may be involved in ICP-associated pruritus. NEW & NOTEWORTHY Fetal placental macrophages and, to a lesser extent, trophoblast cells express high levels of autotaxin at term. An increased expression of mRNA and protein autotaxin, the key secretory enzyme responsible for the production of lysophosphatidic acid in serum, has been observed in placentas of women with cholestasis of pregnancy, which supports that the placenta can contribute to an increased production of this pruritogenic compound in women suffering from this liver disease.
妊娠肝内胆汁淤积症（ICP）常伴有瘙痒，其病因与磷脂酶 A1/A2（PLA1/PLA2）和自分泌运动因子（ATX）的联合作用增强溶血磷脂酸（LPA）的产生有关。在这里，我们研究了 ICP 期间胎盘是否参与 LPA 向母体循环的释放。ICP 妇女的血清 ATX 和 LPA 水平（通过 ELISA 测定）升高，并且发现这两个参数之间存在相关性。未发现血清 ATX 或 LPA 水平与胆汁酸之间存在任何关系。通过 RT-qPCR 和 Western blot 测定 ATX 和 PLA2 的表达水平。ICP 中胎盘 ATX 但不是 PLA2 表达显著上调，并且在蛋白质水平上发现有增加的趋势。发现血清 ATX 与胎盘 ATX mRNA 水平之间存在相关性。在足月人胎盘，（通过免疫荧光）清楚地检测到 Hofbauer 细胞中的 ATX，但在滋养细胞中仅微弱检测到。在怀孕的大鼠中，胎盘的 Atx 和 Pla2 表达低于肝脏。当从妊娠第 14 天起通过胆管结扎施加阻塞性胆汁淤积症直至足月时，胎盘 Atx 和 Pla2 的表达明显增强，并且在蛋白质水平上确认了 Pla2 的过表达，而 ATX 蛋白未检测到。总之，胎盘在妊娠期间大量参与 LPA 的产生。在母体胆汁淤积时，这种贡献明显更高，因此可能与 ICP 相关的瘙痒有关。新的和值得注意的是，胎儿胎盘巨噬细胞和程度较小的滋养层细胞在足月时表达高水平的自分泌运动因子。在患有妊娠胆汁淤积症的妇女的胎盘观察到 mRNA 和蛋白质自分泌运动因子的表达增加，自分泌运动因子是负责在血清中产生溶血磷脂酸的关键分泌酶，这支持了胎盘可以有助于增加患有这种肝脏疾病的妇女中这种瘙痒化合物的产生。
