Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation
Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation
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DOI：
10.1152/ajpgi.00144.2007
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Murase, Noriko
中科院分区：
文献类型：
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作者：
Kaizu, Takashi;Ikeda, Atsushi;Murase, Noriko
一氧化碳 (CO) 是血红素加氧酶 (HO) 降解血红素的产物，已被证明可以在各种组织损伤模型中提供细胞保护。本研究探讨了外源吸入 CO 保护肝移植物免受肝移植相关冷缺血/再灌注 (I/R) 损伤的功效和分子机制。对Lewis大鼠进行原位同基因肝移植（OLT），并在威斯康星大学溶液中冷藏18小时。受体在 OLT 前 1 小时和 OLT 后 24 小时暴露在空气或不同浓度的 CO (20-250 ppm) 中，并在移植后 1-48 小时处死。 OLT后24-48小时，CO吸入可显着降低血清丙氨酸转氨酶（ALT）水平，并以剂量依赖性方式抑制肝坏死和中性粒细胞积累。吸入 CO 减少的肝损伤与 TNF-α 和 IL-6 早期 mRNA 表达的显着下调有关。 CO 显着降低了肝移植物中应激反应酶诱导型一氧化氮合酶 mRNA 和蛋白的表达，而 HO-1 仅受到轻微抑制。冷肝I/R损伤与OLT后1小时移植肝中MAPK迅速磷酸化有关，CO显着抑制ERK1/2 MAPK及其上游MEK1/2和下游转录因子c-Myc的磷酸化。 CO 还显着抑制 I/R 损伤诱导的 STAT1 和 STAT3 激活。相比之下，CO 在肝 I/R 损伤期间不会抑制 p38 或 JNK MAPK 通路。结果表明，外源性 CO 抑制早期促炎和应激反应基因表达，并有效改善肝缺血再灌注损伤。可能的机制可能包括CO下调MEK/ERK1/2信号通路。
Carbon monoxide (CO), a product of heme degradation by heme oxygenases (HO), has been shown to provide cytoprotection in various tissue injury models. This study examined the efficacy and molecular mechanisms of exogenously delivered inhaled CO in protecting liver grafts from cold ischemia/reperfusion (I/R) injury associated with liver transplantation. Orthotopic syngenic liver transplantation (OLT) was performed in Lewis rats with 18-h cold preservation in University of Wisconsin solution. Recipients were exposed to air or different concentrations of CO (20-250 ppm) for 1 h before and 24 h after OLT and killed 1-48 h posttransplant. CO inhalation significantly decreased serum alanine transaminase (ALT) levels and suppressed hepatic necrosis and neutrophil accumulation at 24-48 h after OLT in a dose-dependent manner. Reduced hepatic injury with inhaled CO is associated with marked downregulation of early mRNA expression for TNF-alpha and IL-6. Expression in liver grafts of mRNA and protein of the stress-responding enzyme inducible nitric oxide synthase was significantly reduced by CO, while HO-1 was only marginally suppressed. Cold hepatic I/R injury was associated with prompt MAPK phosphorylation in liver grafts at 1 h after OLT, and CO significantly inhibited phosphorylation of ERK1/2 MAPK and its upstream MEK1/2 and downstream transcriptional factor c-Myc. CO also significantly inhibited I/R injury-induced STAT1 and STAT3 activation. In contrast, CO did not inhibit p38 or JNK MAPK pathways during hepatic I/R injury. Results demonstrate that exogenous CO suppresses early proinflammatory and stress-response gene expression and efficiently ameliorates hepatic I/R injury. The possible mechanism may include the downregulation of MEK/ERK1/2 signaling pathway with CO.