Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor
Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor
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DOI：
10.1124/jpet.107.128264
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Claria, Joan
中科院分区：
文献类型：
--
作者：
Horrillo, Raquel;Planaguma, Anna;Claria, Joan
在这项研究中，我们研究了环氧合酶-2（考克斯-2）和5-脂氧合酶（5-LO）的相对贡献，这两种主要的促炎途径在肝脏疾病中上调，以促进肝脏炎症和纤维化的进展。对四氯化碳处理的小鼠分别给予4-[5-（4-氯苯基）-3-（三氟甲基）-1H-吡唑-1-基]苯磺酰胺（SC-236）（一种选择性考克斯-2抑制剂）和CJ-13，610（一种5-LO抑制剂）可显著减少纤维化，如天狼星红染色的肝切片分析所示，而不影响坏死性炎症。相反，SC-236和4-[3-[4-（2-甲基咪唑-1-基）-苯硫基]]苯基-3，4，5，6-四氢-2H-吡喃-4-甲酰胺（CJ-13，610）联合给药可减少坏死性炎症和纤维化。这些发现在接受SC-236的5-LO缺陷小鼠中得到证实，其也显示肝单核细胞趋化蛋白1表达降低。有趣的是，SC-236和CJ-13，610显著增加了具有凋亡核的非实质肝细胞的数量（末端脱氧核苷酸转移酶dUTP缺口末端标记阳性）。在巨噬细胞（原发性肝脏炎症细胞类型）中进行了SC-236和CJ-13，610的其他药理学分析。在这些细胞中，SC-236以浓度依赖性方式抑制前列腺素（PG）E-2的形成，而CJ-13，610阻断白三烯B-4的生物合成。值得注意的是，同时加入SC-236和CJ-13，610导致对PGE（2）生物合成的抑制作用比双重考克斯/5-LO抑制剂licofelone更高。这些药物差异调节巨噬细胞中白细胞介素-6 mRNA的表达。总之，这些发现表明，考克斯-2和5-LO途径都是肝脏炎症和纤维化的促成因素，并且花生四烯酸级联的这两个途径代表了治疗的潜在靶点。
In this study, we examined the relative contribution of cyclo-oxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), two major proinflammatory pathways up-regulated in liver disease, to the progression of hepatic inflammation and fibrosis. Separate administration of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H- pyrazol-1-yl]benzenesulfonamide (SC-236), a selective COX-2 inhibitor, and CJ-13,610, a 5-LO inhibitor, to carbon tetrachloride-treated mice significantly reduced fibrosis as revealed by the analysis of Sirius Red-stained liver sections without affecting necroinflammation. Conversely, combined administration of SC-236 and 4-[3-[4-(2-methylimidazol-1-yl)-phenylthio]] phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (CJ-13,610) reduced both necroinflammation and fibrosis. These findings were confirmed in5-LO-deficient mice receiving SC-236, which also showed reduced hepatic monocyte chemoattractant protein 1 expression. Interestingly, SC-236 and CJ-13,610 significantly increased the number of nonparenchymal liver cells with apoptotic nuclei ( terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive). Additional pharmacological profiling of SC-236 and CJ-13,610 was performed in macrophages, the primary hepatic inflammatory cell type. In these cells, SC-236 inhibited prostaglandin (PG) E-2 formation in a concentration-dependent manner, whereas CJ-13,610 blocked leukotriene B-4 biosynthesis. Of note, the simultaneous addition of SC-236 and CJ-13,610 resulted in a higher inhibitory profile on PGE(2) biosynthesis than the dual COX/5-LO inhibitor licofelone. These drugs differentially regulated interleukin-6 mRNA expression in macrophages. Taken together, these findings indicate that both COX-2 and 5-LO pathways are contributing factors to hepatic inflammation and fibrosis and that these two pathways of the arachidonic acid cascade represent potential targets for therapy.