KUPFFER CELL ACTIVATION BY HYDROGEN PEROXIDE: A NEW MECHANISM OF PORTAL PRESSURE INCREASE
KUPFFER CELL ACTIVATION BY HYDROGEN PEROXIDE: A NEW MECHANISM OF PORTAL PRESSURE INCREASE
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过氧化氢激活枯否细胞：门静脉压力增加的新机制
作者：
C. Steib;M. Bilzer;Josef M. Härtl;Frigga Beitinger;V. Gülberg;B. Göke;A. Gerbes
本研究旨在研究活性氧对肝巨噬细胞、枯否细胞(KC)的影响，并确定参与调节肝内微循环及门脉压力的血管收缩物质的相关靶点。在假手术和肝纤维化大鼠肝脏(胆管结扎4周以上)上，观察了过氧化氢(H_2O_2)、黄嘌呤/黄嘌呤氧化酶或血栓素(TX)类似物(U46619；0.1&Mgr；M)在肝脏灌流和体内应用KC阻滞剂(Gd，10 mg·kg~(-1)−_1体重，48和24小时，ip.为了研究下游机制，另外注入TXA2拮抗剂(BM 13.177；20)或Rho激酶抑制剂(Y27632；10&Mgr；M)。采用酶联免疫吸附试验测定TXB_2外排。用Western印迹法检测作为Rho激酶活性指标的Moesin(p-moesin)的磷酸化状态。H_2O_2(最大0.5 mM)可剂量依赖性地增加门脉压力，黄嘌呤/黄嘌呤氧化酶和过氧化氢酶对门静脉压力的影响较小。KC阻滞剂可减弱H_2O_2引起的门脉压力升高。注射H_2O_2后TXA_2外流增加，KC阻断后TXA_2外流减少。TXA2拮抗剂可拮抗H_2O_2诱导的门静脉压力升高。Rho激酶抑制剂可减轻TXA2类似物或H_2O_2输注后门脉压力的升高。H_2O_2注射后肝脏p-moesin水平升高。活性氧通过刺激KCs产生TXA2和随后依赖Rho激酶的肝内血管收缩来增加门脉压力。综上所述，已知能产生过氧化氢的KCs也可以被过氧化氢激活。这一恶性循环最好在最早的时间点被打断。U-46619，9，11-Dideoxy-9-11-methanoepoxy-prostaglandin-胆管结扎术；BM 13.177-溶质；二甲基亚砜；过氧化氢；GdCl3-氯化Gd；KC-库普弗细胞；O2-−-超氧阴离子；ROS-活性氧物种；TX-血栓烷；BM-F2；KC-库普弗细胞；
This study aimed to investigate the effects of reactive oxygen species on the hepatic macrophages, the Kupffer cells (KC), and to identify the relevant targets of vasoconstrictors involved in the regulation of intrahepatic microcirculation and therefore portal pressure. The effects of hydrogen peroxide (H2O2), xanthine/xanthine oxidase or a thromboxane (TX) analogue (U46619; 0.1 &mgr;M) were tested in sham-operated and fibrotic livers (bile duct ligation over 4 weeks) during isolated rat liver perfusion and in vivo with or without additional KC blockade (gadolinium chloride, 10 mg kg−1 body weight, 48 and 24 h, i.p.). To investigate downstream mechanisms, a TXA2 antagonist (BM 13.177; 20 &mgr;M) or a Rho kinase inhibitor (Y27632; 10 &mgr;M) was infused additionally. TXB2 efflux was measured by enzyme-linked immunosorbent assay. The phosphorylation state of moesin (p-moesin), as indicator for Rho kinase activity, was assessed by Western blot analyses. Portal pressure was dose-dependently increased by H2O2 (maximum, 0.5 mM) and, to a lower extent, by xanthine/xanthine oxidase together with catalase. The portal pressure increase by H2O2 was attenuated by previous KC blockade. TXA2 efflux increased after H2O2 infusion and was reduced by KC blockade. The TXA2 antagonist counteracted the H2O2-induced increase in portal pressure. The Rho kinase inhibitor attenuated portal pressure increase after TXA2 analogue or H2O2 infusion. Hepatic levels of p-moesin were increased after H2O2 infusion. Reactive oxygen species increased portal pressure via stimulation of TXA2 production by KCs and a subsequent Rho kinase-dependent contraction of the intrahepatic vasculature. In conclusion, the KCs that are well known to produce H2O2 could also be activated by H2O2. This vicious cycle may best be interrupted at the earliest time point.ABBREVIATIONS-BDL-bile duct ligation; BM 13.177-solutroban; DMSO-dimethyl sulfoxide; H2O2-hydrogen peroxide; GdCl3-gadolinium chloride; KC-Kupffer cell; O2−.-superoxide anion; ROS-reactive oxygen species; TX-thromboxane; U-46619,9,11-Dideoxy-9-11-methanoepoxy-prostaglandin F2; Y-27632-(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride
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影响因子：
29.4
作者：
Krohn N;Kapoor S;Enami Y;Follenzi A;Bandi S;Joseph B;Gupta S
通讯作者：
Gupta S
DOI：
10.1152/ajpgi.00297.2005
发表时间：
2006-03-01
影响因子：
4.5
作者：
Perri, RE;Langer, DA;Shah, VH
通讯作者：
Shah, VH
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
发表时间：
2005
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
--
作者：
Xu,Hongzhi;Korneszczuk,Katarzyna;Karaa,Amel;Lin,Tian;Clemens,MarkG;Zhang,JianX
通讯作者：
Zhang,JianX
DOI：
10.1152/ajpgi.00143.2003
发表时间：
2003-09-01
影响因子：
4.5
作者：
Hendrickson, H;Chatterjee, S;Shah, V
通讯作者：
Shah, V