Thromboxane A2 from Kupffer cells contributes to the hyperresponsiveness of hepatic portal circulation to endothelin-1 in endotoxemic rats.
Thromboxane A2 from Kupffer cells contributes to the hyperresponsiveness of hepatic portal circulation to endothelin-1 in endotoxemic rats.
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内毒素血症大鼠中，库普弗细胞中的血栓素 A2 导致肝门循环对内皮素-1 的高反应性。
DOI：
10.1152/ajpgi.00256.2004
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Zhang,JianX
中科院分区：
文献类型：
--
作者：
Xu,Hongzhi;Korneszczuk,Katarzyna;Karaa,Amel;Lin,Tian;Clemens,MarkG;Zhang,JianX
我们研究了血栓素A2(TXA2)在内毒素诱导的肝门脉循环对内毒素(ETS)高反应性中的作用，以及Kupffer细胞是否是内毒素血症中ET-1释放TXA2的主要来源。内毒素(1 mg/kg体重体重，ip)或生理盐水(对照组)注射6h后，分离肝脏，以恒定流量(100ml.min−1·kg体重体重−1)灌流。ET-1(10pmol/min)灌流10min。在灌流过程中持续监测门脉压力(PP)。取灌流液行血栓素B2(TXB2，血栓素A2的稳定代谢产物)酶免疫测定和乳酸脱氢酶(LDH)测定。注射ET-1后，内毒素组大鼠的脉压升高幅度明显大于对照组。TXA2合成酶抑制剂Furegrelate(Fureg)和TXA2受体拮抗剂SQ-29548(SQ)均显著阻断内毒素组PP的增加(分别为4.9±0.4vs.3.6±0.5vs.2.6±0.6 mm Hg，P<0.0 5)，而对对照组无明显影响。GdCl3对Kupffer细胞的抑制作用相似(分别为4.9±0.4 mm Hg和2.9±0.4 mm Hg；P<；0.05)。此外，福瑞格、SQ和GdCl3可显著降低ET-1诱导的PP和TXB_2、LDH的释放(分别为886.6±73.4vs.110.8±0.8vs.114.8±54.7vs.135.2±45.2pg/ml，P均<0.05)。在内毒素作用6h后，分离细胞中的Kupffer细胞释放出大量的TXA2，以响应ET-1。这些结果清楚地表明，内毒素血症时肝门循环对ET-1的高反应性至少部分是由TXA2诱导的受体激活所介导的，而Kupffer细胞可能是增加TXA2释放的主要来源。
We examined the role of thromboxane A2(TXA2) in LPS-induced hyperresponsiveness of hepatic portal circulation to endothelins (ETs) and whether Kupffer cells are the primary source of TXA2release in response to ET-1 in endotoxemia. After 6 h of LPS (1 mg/kg body wt ip) or saline (control), liver was isolated and perfused with recirculating Krebs-Henseleit bicarbonate buffer at a constant flow rate (100 ml·min−1·kg body wt−1). ET-1 (10 pmol/min) was infused for 10 min. Portal pressure (PP) was continuously monitored during perfusion. Perfusate was sampled for enzyme immunoassay of thromboxane B2(TXB2; the stable metabolite of TXA2) and lactate dehydrogenase (LDH) assay. ET-1 infusion resulted in a significantly greater increase of PP in the LPS group than in controls. Both TXA2synthase inhibitor furegrelate (Fureg) and TXA2receptor antagonist SQ-29548 (SQ) substantially blocked enhanced increase of PP in the LPS group (4.9 ± 0.4 vs. 3.6 ± 0.5 vs. 2.6 ± 0.6 mmHg for LPS alone, LPS + Fureg, and LPS + SQ, respectively;P< 0.05) while having no significant effect on controls. GdCl3for inhibition of Kupffer cells had similar effects (4.9 ± 0.4 mmHg vs. 2.9 ± 0.4 mmHg for LPS alone and GdCl3+ LPS, respectively;P< 0.05). In addition, the attenuated PP after ET-1 was found concomitantly with significantly decreased releases of TXB2and LDH in LPS rats treated with Fureg, SQ, and GdCl3(886.6 ± 73.4 vs. 110.8 ± 0.8 vs. 114.8 ± 54.7 vs. 135.2 ± 45.2 pg/ml, respectively;P< 0.05). After 6 h of LPS, Kupffer cells in isolated cell preparations released a significant amount of TXA2in response to ET-1. These results clearly indicate that hyperresponsiveness of hepatic portal circulation to ET-1 in endotoxemia is mediated at least in part by TXA2-induced receptor activation, and Kupffer cells are likely the primary source of increased TXA2release.
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