Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine.
Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine.
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DOI：
10.1124/jpet.107.122069
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发表时间：
2007-08
期刊：
影响因子：
--
通讯作者：
Roth RA
中科院分区：
文献类型：
--
作者：
Deng X;Luyendyk JP;Zou W;Lu J;Malle E;Ganey PE;Roth RA
用无毒剂量的雷尼替丁（RAN）和脂多糖（LPS）联合治疗大鼠会引起肝损伤，这种药物-炎症相互作用可能是人类特异质不良药物反应的模型。多形核中性粒细胞（PMN）和止血系统已被证明是重要的损伤。我们检验了中性粒细胞通过与止血系统相互作用并产生随后的缺氧而引起肝损伤的假设。在LPS/RAN共处理的大鼠中，抗PMN血清消耗PMN减少肝脏中的纤维蛋白沉积和缺氧。PMN耗竭也降低了血浆中纤溶酶原激活物抑制剂-1（派-1）的浓度，PAI-1是纤溶系统的主要下调因子。这表明PMN通过增加派-1浓度促进纤维蛋白沉积。LPS/RAN共处理的大鼠肝脏中的PMN被激活，这一点通过活化吞噬细胞的髓过氧化物酶-过氧化氢-氯化物系统产生的次氯酸修饰蛋白的染色增加来证明。针对中性粒细胞粘附分子CD 18的抗血清可防止LPS/RAN诱导的肝损伤。由于CD 18对PMN的迁移和活化非常重要，这些结果表明，PMN活化是肝损伤所必需的。此外，抗CD 18血清减少止血和缺氧的生物标志物，表明PMN活化的必要性，在PMN和止血系统/缺氧之间的相互作用。肝损伤，肝纤维蛋白，血浆派-1浓度也减少了eglin C，激活的中性粒细胞释放的蛋白酶抑制剂。总之，在LPS/RAN共处理的大鼠中，PMN被激活，并通过促进止血和缺氧而部分参与肝损伤。
Cotreatment of rats with nontoxic doses of ranitidine (RAN) and lipopolysaccharide (LPS) causes liver injury, and this drug-inflammation interaction might be a model for idiosyncratic adverse drug responses in humans. Both polymorphonuclear neutrophils (PMNs) and the hemostatic system have been shown to be important in the injury. We tested the hypothesis that PMNs cause liver injury by interacting with the hemostatic system and producing subsequent hypoxia. In rats cotreated with LPS/RAN, PMN depletion by anti-PMN serum reduced fibrin deposition and hypoxia in the liver. PMN depletion also reduced the plasma concentration of active plasminogen activator inhibitor-1 (PAI-1), a major down-regulator of the fibrinolytic system. This suggests that PMNs promote fibrin deposition by increasing PAI-1 concentration. PMNs were activated in the livers of LPS/RAN-cotreated rats as evidenced by increased staining for hypochlorous acid-modified proteins generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes. Antiserum against the PMN adhesion molecule CD18 protected against LPS/RAN-induced liver injury. Because CD18 is important for PMN transmigration and activation, these results suggest that PMN activation is required for the liver injury. Furthermore, anti-CD18 serum reduced biomarkers of hemostasis and hypoxia, suggesting the necessity for PMN activation in the interaction between PMNs and the hemostatic system/hypoxia. Liver injury, liver fibrin, and plasma PAI-1 concentration were also reduced by eglin C, an inhibitor of proteases released by activated PMNs. In summary, PMNs are activated in LPS/RAN-cotreated rats and participate in the liver injury in part by contributing to hemostasis and hypoxia.