Kupffer cell inactivation by carbon monoxide bound to red blood cells preserves hepatic cytochrome P450 via anti-oxidant and anti-inflammatory effects exerted through the HMGB1/TLR-4 pathway during resuscitation from hemorrhagic shock
Kupffer cell inactivation by carbon monoxide bound to red blood cells preserves hepatic cytochrome P450 via anti-oxidant and anti-inflammatory effects exerted through the HMGB1/TLR-4 pathway during resuscitation from hemorrhagic shock
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DOI：
10.1016/j.bcp.2015.07.035
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发表时间：
2015-10-01
影响因子：
5.8
通讯作者：
Maruyama, Toru
中科院分区：
文献类型：
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作者：
Ogaki, Shigeru;Taguchi, Kazuaki;Maruyama, Toru
用于控制出血的红细胞 (RBC) 输注会引起全身缺血再灌注，导致肝细胞色素 P450 (CYP) 水平下降。一氧化碳 (CO) 与红细胞 (CO-RBC) 结合时，有可能保护肝 CYP 蛋白，从而在失血性休克大鼠模型中产生复苏作用。本研究的目的是探讨大出血时 CO-RBC 复苏防止肝脏 CYP 下降的机制。在出血和红细胞复苏后的早期（大约1小时），随着肝游离血红素水平的增加，肝CYP蛋白水平显着降低，但通过氯化钆（GdCl3）（一种库普弗细胞抑制剂）和Trolox（一种抗氧化剂）预处理以及CO-红细胞复苏来维持。在这些条件下，来自活化库普弗细胞的活性氧 (ROS) 的产生增加，但这种增加被 CO-RBC 复苏所抑制。在后期（6 类似于 24 小时），CYP mRNA 水平在出血和 RBC 复苏后下降，但在 CO-RBC 复苏的情况下没有下降。 CO-RBC 复苏通过抑制 Toll 样受体 4 (TLR-4) 和高迁移率族蛋白盒 1 (HMGB-1) 的表达，降低了血浆 IL-6 和 TNF-α 水平的增加。出血和CO-RBC复苏后的肝脏CYP保护可归因于库普弗细胞失活，导致早期ROS产生受到抑制，后期通过TLR-4/HMGB-1信号通路抑制炎症细胞因子产生。 (C) 2015 Elsevier Inc. 保留所有权利。
Red blood cell (RBC) transfusions for controlling hemorrhaging induce systemic ischemia reperfusion, resulting in a decrease in hepatic cytochrome P450 (CYP) levels. Carbon monoxide (CO), when bound to red blood cells (CO-RBC) has the potential to protect the hepatic CYP protein to produce a resuscitative effect in a hemorrhagic shock rat model. The aim of this study was to investigate the mechanism by which CO-RBC resuscitation from a massive hemorrhage protects against a decrease in hepatic CYP. In the early phase (similar to 1 h) after a hemorrhage and RBC resuscitation, hepatic CYP protein levels were significantly decreased with increasing hepatic free heme levels, but were maintained by a pre-treatment of gadolinium chloride (GdCl3), a Kupffer cell inhibitor, and Trolox, an anti-oxidant agent, as well as CO-RBC resuscitation. Under these conditions, the production of reactive oxygen species (ROS) derived from activated Kupffer cells was increased, but this increase was suppressed by CO-RBC resuscitation. At a late phase (6 similar to 24 h), CYP mRNA levels decreased after hemorrhage and RBC resuscitation, but not in the case of CO-RBC resuscitation. The increases in plasma IL-6 and TNF-alpha levels were decreased by CO-RBC resuscitation via the suppression of the toll-like receptor-4 (TLR-4) and the expression of the high mobility group box-1 (HMGB-1). Hepatic CYP protection after a hemorrhage and CO-RBC resuscitation can be attributed to the inactivation of Kupffer cells, resulting in the suppression of ROS production in the early phase and the suppression of inflammatory cytokine production via the TLR-4/HMGB-1 signal pathway in the late phase. (C) 2015 Elsevier Inc. All rights reserved.