CO liberated from CORM-2 modulates the inflammatory response in the liver of thermally injured mice.
CO liberated from CORM-2 modulates the inflammatory response in the liver of thermally injured mice.
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DOI：
10.3748/wjg.14.547
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发表时间：
2008-01
影响因子：
4.3
通讯作者：
Bingwei Sun;Yan Sun;Zhi-wei Sun;X. Chen
中科院分区：
文献类型：
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作者：
Bingwei Sun;Yan Sun;Zhi-wei Sun;X. Chen
目的探讨CO释放分子CORM-2释放的CO减轻热损伤动物肝脏炎症反应的作用及其可能机制。方法36只小鼠分为3组，分别进行3个实验。在每个实验中，假手术组（n=4）中的小鼠接受假热损伤，而烧伤组（n=4）中的小鼠接受总体表面积（TBSA）的15%的全层热损伤，并且烧伤+CORM-2组（n=4）中的小鼠接受相同的热损伤并立即给予CORM-2（8 mg/kg，iv）。肝组织切片用苏木精和伊红染色，并在光学显微镜下检查。生化法检测血清转氨酶（ALT、AST）和一氧化氮（NO）水平。检测血清和组织匀浆中肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1 β）的活性以及iNOS和HO-1的蛋白表达。在体外实验中，在存在或不存在CORM-2（10-100 μ mol/L）的情况下，用LPS（10 μ g/mL）刺激枯否细胞4小时。随后，评估TNF-α和NO产生的表达水平。结果CORM-2能显著降低热损伤小鼠血清和肝组织匀浆中TNF-α、IL-1 β、NO的含量。肝组织中iNOS的表达减少，HO-1的表达增加。与此同时，LPS刺激的Kupffer细胞与CORM-2（10-100 μ mol/L）共孵育的上清液中TNF-α和NO的浓度也显著降低。组织学检查表明CORM-2可减轻白细胞向肝组织的浸润。结论CORM释放的CO通过抑制iNOS和NO的表达，下调TNF-α、IL-1 β的表达，调节烧伤小鼠肝脏炎症反应，对肝损伤具有保护作用。
AIM To explore the effects of CO-releasing molecules [tricarbonyldichlororuthenium (II) dimer, CORM-2]-liberated CO on attenuation of inflammatory responses in liver of an experimental animal model of thermal injury and to investigate the associated potential mechanisms. METHODS Thirty-six mice were assigned to three groups in three respective experiments. In each experiment, mice in sham group (n=4) received sham thermal injury, whereas mice in burn group (n=4) received a 15% of total body surface area (TBSA) full-thickness thermal injury, and mice in burn+CORM-2 group (n=4) received the same thermal injury with immediate administration of CORM-2 (8 mg/kg, iv). Hepatic tissue sections were stained with hematoxylin and eosin and examined under a light microscope. Levels of aminotransferases (ALT and AST) and nitric oxide (NO) were measured by biochemical methods. Tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL-1beta) activity, and the protein expression of iNOS and HO-1 in serum and tissue homogenates were assessed. In in vitro experiments, Kupffer cells were stimulated with LPS (10 microg/mL) for 4 h in the presence or absence of CORM-2 (10-100 micromol/L). Subsequently, the expression levels of TNF-alpha and NO production were assessed. RESULTS Pro-inflammatory mediators (TNF-alpha, IL-1beta, NO) in serum and liver homogenates of thermally injured mice were significantly reduced by CORM-2 administration. This was accompanied by a decrease in the expression of iNOS while an increase in the expression of HO-1 in the liver tissue. In parallel, the concentrations of TNF-alpha and NO in supernatants of LPS-stimulated Kupffer cells co-incubated with CORM-2 (10-100 micromol/L) were also markedly decreased. Histological examination demonstrated that CORM-2 could attenuate the leukocytes infiltration to the liver tissue. CONCLUSION CORM-released CO modulates liver inflammation and significantly protects liver injury in burn mice by inhibiting the expression of iNOS and NO production, down-regulating the expression of pro-inflammatory mediators (TNF-alpha, IL-1beta).