Flavocoxid, a dual inhibitor of COX-2 and 5-LOX of natural origin, attenuates the inflammatory response and protects mice from sepsis.
Flavocoxid, a dual inhibitor of COX-2 and 5-LOX of natural origin, attenuates the inflammatory response and protects mice from sepsis.
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DOI：
10.1186/1364-8535-16-r32
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发表时间：
2012-02-22
期刊：
影响因子：
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通讯作者：
Altavilla D
中科院分区：
文献类型：
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作者：
Bitto A;Minutoli L;David A;Irrera N;Rinaldi M;Venuti FS;Squadrito F;Altavilla D
盲肠结扎穿刺（CLP）是一种炎症性疾病，可导致多系统器官功能衰竭。黄酮是一种环氧化酶（COX-2）和5-脂氧化酶（5-LOX）的双重抑制剂，体外研究表明，黄酮通过降低核因子(NF)-κB活性和cox - 2,5 - lox和诱导型一氧化氮合酶（iNOS）的表达，在脂多糖（LPS）刺激的大鼠巨噬细胞中具有抗炎活性。本研究的目的是评估黄酮类化合物在clp诱导的多微生物脓毒症小鼠模型中的作用。C57BL/6J小鼠分别进行CLP或假手术。在第一组实验中，术后1小时腹腔注射黄酮类化合物（20mg /kg）或对照物，每12小时重复一次。120小时内每24小时监测一次存活率。此外，在手术后18小时杀死另外几组假和CLP小鼠进行血液采集，并收集肺和肝脏进行生物分子、生化和组织病理学研究。Western blot检测肺、肝组织中cox - 2,5 - lox、肿瘤坏死因子-α (TNF-α)、白细胞介素(IL)-6、IL-10、细胞外调节激酶1/2 （ERK）、jun -末端激酶（JNK）、NF-κB、β-阻滞蛋白2蛋白的表达。此外，采用酶联免疫吸附试验（ELISA）测定血清白三烯B4 （LTB4）、前列腺素E2 （PGE2）、细胞因子和脂素A4的含量。黄酮可提高生存率，降低NF-κB、COX-2、5-LOX、TNF-α和IL-6的表达，增加IL-10的产生。此外，黄酮类化合物抑制丝裂原活化蛋白激酶（MAPKs）通路，保持β-阻滞蛋白2的表达，降低血液中LTB4、PGE2、TNF-α和IL-6，升高血清中IL-10和脂素A4水平。黄酮类化合物治疗还可以防止CLP引起的组织学损伤，降低肺和肝脏的髓过氧化物酶（MPO）活性。黄酮类化合物可以保护小鼠免受败血症的侵害，这表明这种双重抑制剂可能在这种危及生命的情况下代表了一种有希望的方法。
Cecal ligation and puncture (CLP) is an inflammatory condition that leads to multisystemic organ failure. Flavocoxid, a dual inhibitor of cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX), has been shown in vitro to possess antiinflammatory activity in lipopolysaccharide (LPS)-stimulated rat macrophages by reducing nuclear factor (NF)-κB activity and COX-2, 5-LOX and inducible nitric oxide synthase (iNOS) expression. The aim of this study was to evaluate the effects of flavocoxid in a murine model of CLP-induced polymicrobial sepsis. C57BL/6J mice were subjected to CLP or sham operation. In a first set of experiments, an intraperitoneal injection of flavocoxid (20 mg/kg) or vehicle was administered 1 hour after surgery and repeated every 12 hours. Survival rate was monitored every 24 hours throughout 120 hours. Furthermore, additional groups of sham and CLP mice were killed 18 hours after surgical procedures for blood-sample collection and the lung and liver were collected for biomolecular, biochemical and histopathologic studies. COX-2, 5-LOX, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, extracellular-regulated-kinase 1/2 (ERK), JunN-terminal kinase (JNK), NF-κB, and β-arrestin 2 protein expression were evaluated in lung and liver with Western blot analysis. In addition, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), cytokines, and lipoxin A4 serum content were measured with an enzyme-linked immunosorbent assay (ELISA). Flavocoxid administration improved survival, reduced the expression of NF-κB, COX-2, 5-LOX, TNF-α and IL-6 and increased IL-10 production. Moreover, flavocoxid inhibited the mitogen-activated protein kinases (MAPKs) pathway, preserved β-arrestin 2 expression, reduced blood LTB4, PGE2, TNF-α and IL-6, and increased IL-10 and lipoxin A4 serum levels. The treatment with flavocoxid also protected against the histologic damage induced by CLP and reduced the myeloperoxidase (MPO) activity in the lung and liver. Flavocoxid protects mice from sepsis, suggesting that this dual inhibitor may represent a promising approach in such a life-threatening condition.