Effects of carbon monoxide releasing molecule-liberated CO on severe acute pancreatitis in rats
Effects of carbon monoxide releasing molecule-liberated CO on severe acute pancreatitis in rats
复制标题
一氧化碳释放分子CO对大鼠重症急性胰腺炎的影响
DOI：
10.1016/j.cyto.2009.09.013
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发表时间：
2010-01-01
期刊：
影响因子：
3.8
通讯作者：
Wang, Shuangjia
中科院分区：
文献类型：
--
作者：
Chen, Ping;Sun, Bei;Wang, Shuangjia
最近的研究表明，外源性一氧化碳(CO)有利于急性炎症的消退。重症急性胰腺炎(SAP)是一种导致全身炎症反应综合征(SIRS)的炎症状态。在本研究中，我们探讨了一氧化碳释放分子-2(CORM-2)在重症急性胰腺炎(SAP)大鼠体内释放CO的作用。胰胆管逆行注入5%牛磺胆酸钠建立SAP模型。将40只Wistar大鼠随机分为4组。假手术组在假手术后给予生理盐水。SAP组在建立SAP模型后给予生理盐水治疗。COMM-2组静脉注射COMM-2(8 mg/kg)。重症急性胰腺炎发病后。ICORM-2组在SAP诱导后给予iCORM-2(一种非活性化合物作为阴性对照)。术后12h处死动物。监测大鼠80只，每组20只，连续监测7d，观察其存活率。在另一组实验中，前三组接受了上述相同的治疗。最后一组于CORM-2注射前1h给予锌PPIX(HO-1抑制剂)，每组10只。测定血清淀粉酶、肿瘤坏死因子-α(TNF-α)、白介素1-β(IL-1β)、白介素10(IL-10)水平及胰腺组织髓过氧化物酶(MPO)活性。观察胰腺的组织学评分、这些细胞因子的mRNA表达、血红素加氧酶-1(HO-1)的表达、HO活性和核因子-kappaB(NF-kappa B)结合活性。结果表明，与SAP组相比，CORM-2治疗组大鼠血清淀粉酶、肿瘤坏死因子-α和IL-1β水平显著降低，胰腺组织中肿瘤坏死因子-α和IL-1β的mRNA表达受到抑制，胰腺组织MPO活性降低。与促炎细胞因子相比，CORM-2可显著提高血清IL-10水平和胰腺组织IL-10的mRNA表达。CORM-2对胰腺组织学的严重程度和存活率也有显著改善。CORM-2治疗与SAP诱导后12小时HO-I表达增加有关。与CORM-2组相比，在SAP形成后12h，给予锌PPIX预处理对这些细胞因子的产生和mRNA表达均无影响。此外，CORM-2处理可抑制胰腺组织中核因子-kappaB的激活。上述结果表明，COMM-2释放的CO对SAP大鼠具有保护作用，其机制可能与抑制核因子-kappaB的活化，进而调节依赖于核因子-kappaB的表达有关。(C)2009爱思唯尔有限公司。保留所有权利。
Recent studies have suggested that exogenously administered carbon monoxide (CO) is beneficial for resolution of acute inflammation. Severe acute pancreatitis (SAP) is an inflammatory condition which leads to a systemic inflammatory response syndrome (SIRS). In this study, we investigated the role of CO liberated from carbon monoxide releasing molecule-2 (CORM-2) in rats with SAP. SAP was induced by retrograde infusion of 5% sodium taurocholate into the pancreatobiliary duct. Forty Wistar rats were randomly divided into four groups. Sham group was given normal saline after the sham operation. SAP group was treated with normal saline after the induction of SAP. CORM-2 group was injected with CORM-2 (8 mg/kg, i.v.) after the onset of SAP. iCORM-2 group was given iCORM-2 (an inactive compound used as negative control) after SAP induction. All animals were sacrificed at 12 h after the operation. Eighty rats (n = 20 for each group) were monitored for 7 days to observe their survival rates. In another set of experiments, the former three groups received the same treatment as mentioned above. The last group was given ZnPPIX (HO-1 inhibitor) by peritoneal injection at I h before the administration of CORM-2 (n = 10 for each group). Serum levels of amylase, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and interleukin 10 (IL-10) as well as myeloperoxidase (MPO) activity in pancreatic tissue were determined. Histological score, mRNA expression of these cytokines, heme oxygenase-1 (HO-1) expression, HO activity, and nuclear factor kappa B (NF-kappa B)-binding activity in the pancreas were also evaluated. Our results showed that compared with SAP group, CORM-2 treatment significantly reduced the serum levels of amylase, TNF-alpha, and IL-1 beta, suppressed pancreatic tissue mRNA expression of TNF-alpha and IL-1 beta, and decreased MPO activity in the pancreas. In contrast with the pro-inflammatory cytokines, the serum level and pancreatic tissue mRNA expression of IL-10 were markedly increased by the injection of CORM-2. The severity of pancreatic histology and survival rate were also significantly improved by the administration of CORM-2. Treatment with CORM-2 was associated with an increase in HO-I expression at 12 h after SAP induction. Pretreatment with ZnPPIX had no effect on the production and mRNA expression of these cytokines at 12 h after the development of SAP with the treatment of CORM-2 as compared to CORM-2 group. Furthermore, CORM-2 treatment inhibited the activation of NF-kappa B in the pancreas. These results indicate that CORM-2-liberated CO exerts protective effects on SAP in rats, and the beneficial effects may be due to the suppression of NF-kappa B activation and subsequent regulation of NF-kappa B-dependent expression of cytokines. (C) 2009 Elsevier Ltd. All rights reserved.