OBJECTIVE:The cytoprotective enzyme heme oxygenase 1 (HO-1) is highly up-regulated in acute pancreatitis (AP). In this study, we tested its metabolites as potential therapeutic agents for AP in rats. METHODS:Acute necrotizing pancreatitis was induced by retrograde intraductal injection of sodium taurocholate in rats. Biliverdin hydrochloride (BV HCl) (50 μmol/kg subcutaneously), the carbon monoxide, donor methylene chloride (MC) (500 mg/kg orally), or iron-chelating desferrioxamine (DFO) (125 mg/kg subcutaneously) were administered in a therapeutic manner starting with the first dose 4 hours after taurocholate injection to mimic the effects of HO-1 metabolites. RESULTS:Administration of BV HCl, MC, or DFO showed significant reduction of inflammatory activity in comparison to controls leading to lower myeloperoxidase activity in the pancreas, less edema, lower ascites volumes, and preservation of tissue integrity (P < 0.05). Administration of either BV HCl or MC markedly increased 5-day survival rate (70% and 75% vs 40%; P < 0.05), whereas DFO had no significant effect on survival (60%). When given in therapeutic manner, all 3 substances led to diminished nuclear factor κB activity in the pancreas (P < 0.05). CONCLUSIONS:Therapeutic use of BV HCl and MC led to marked reduction of mortality in experimental pancreatitis. Thus, HO-1 metabolites may present a novel therapeutic approach in AP treatment.

译文

目的:细胞保护酶血红素加氧酶1(HO-1)在急性胰腺炎(AP)中高度上调。在这项研究中,我们测试了其代谢物作为大鼠AP的潜在治疗剂。
方法:逆行导管内注射牛磺胆酸钠可诱发急性坏死性胰腺炎。皮下注射盐酸Biliverdin(BV HCl)(50μmol/ kg),皮下注射一氧化碳,施主二氯甲烷(MC)(500 mg / kg)或铁螯合去铁胺(DFO)(125 mg / kg)。从牛磺胆酸盐注射后4小时的第一剂开始,以模拟HO-1代谢产物的作用。
结果:与对照组相比,BV HCl,MC或DFO的给药显示出炎性活性显着降低,从而导致胰腺中的髓过氧化物酶活性降低,水肿减少,腹水量减少以及组织完整性得到保护(P <0.05)。 BV HCl或MC的给药显着提高了5天生存率(70%和75%对40%; P <0.05),而DFO对生存期无显着影响(60%)。当以治疗方式给予时,所有这三种物质均导致胰腺中核因子κB活性降低(P <0.05)。
结论:BV HCl和MC的治疗性使用可显着降低实验性胰腺炎的死亡率。因此,HO-1代谢物可能为AP治疗提供一种新颖的治疗方法。

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