The nociceptin/orphanin FQ-NOP receptor antagonist effects on an animal model of sepsis
The nociceptin/orphanin FQ-NOP receptor antagonist effects on an animal model of sepsis
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DOI：
10.1007/s00134-008-1313-3
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发表时间：
2008-12-01
影响因子：
38.9
通讯作者：
Dal-Pizzol, Felipe
中科院分区：
文献类型：
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作者：
Carvalho, Dickson;Petronilho, Fabricia;Dal-Pizzol, Felipe
目的：本研究的目的是研究内源性N/OFQ肽受体（NOP）配体和选择性NOP拮抗剂N/OFQ中的伤害感受素（N/OFQ）和（[Nphe（1）s，Arg（14），Lys（15）]N/OFQ-NH 2）（UFP-101）在大鼠盲肠结扎穿孔（CLP）脓毒症模型后炎症反应中的作用。动物基础科学实验室。对象：雄性Wistar大鼠，体重300-350 g。干预措施：用N/OFQ治疗遭受CLP的大鼠（0.001、0.01或0.1 mg/kg）或UFP-101（0.03、0.03或0.3 mg/kg），术后立即皮下给药。手术后12小时，通过心脏穿刺收集血液，并进行支气管肺泡（BAL）和腹腔灌洗。在一组单独的实验中，监测CLP大鼠10天，评价死亡率。我们的研究结果显示，UFP-101（0.03 mg/kg，sc，但不是0.003 mg/kg）通过有效地防止细胞迁移、细菌传播和通过调节促炎细胞因子和趋化因子的释放来改变与全身炎症反应相关的参数，并降低脓毒症的临床相关模型中的动物死亡率。相比之下，N/OFQ（0.1毫克/公斤，SC）增加死亡率在CLP model.Conclusions：我们的研究结果点的N/OFQ-NOP受体系统和炎症反应在CLP模型脓毒症之间的功能关系，并建议NOP受体拮抗剂是值得测试的创新药物用于治疗脓毒症。
Objective: The aim of this study was investigate the effects of nociceptin/orphanin FQ (N/OFQ) and ([Nphe(1)s, Arg(14), Lys(15)]N/OFQ-NH2) (UFP-101), the endogenous N/OFQ peptide receptor (NOP) ligand and a selective NOP antagonist, respectively, in the inflammatory response after cecal ligation and puncture (CLP) model of sepsis in rats.Design: Prospective, controlled experiment.Setting: Animal basic science laboratory.Subjects: Male Wistar rats, weighing 300-350 g.Interventions: Rats subjected to CLP were treated with N/OFQ (0.001, 0.01 or 0.1 mg/kg) or UFP-101 (0.03, 0.03 or 0.3 mg/kg) subcutaneously administered immediately after surgery.Measruements and main results: Twelve hours after surgery, blood was collected by cardiac puncture and bronchoalveolar (BAL) and peritoneal lavage were performed. In a separate set of experiments mortality was evaluated monitoring CLP rats for 10 days. Our findings showed that UFP-101 (0.03 mg/kg, sc, but not 0.003 mg/kg) modified parameters related to the systemic inflammatory response by effectively preventing cells migration, bacterial dissemination, and by modulating the release of pro-inflammatory cytokines and chemokines, and reducing animal mortality in a clinically relevant model of sepsis. By contrast, N/OFQ (0.1 mg/kg, sc) increased mortality in the CLP model.Conclusions: Our findings point to a functional relationship between the N/OFQ-NOP receptor system and inflammatory response in the CLP model of sepsis and suggest that NOP receptor antagonists are worthy of testing as innovative drugs for the treatment of sepsis.