Thomas Roisin C, Bath Michael F, Stover Cordula M, Lambert David G, Thompson Jonathan P
Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom.
Department of Infection, Inflammation and Immunity, University of Leicester, Medical Sciences Building, University Road, Leicester LE1 9HN, United Kingdom.
Peptides. 2014 Nov;61:56-60. doi: 10.1016/j.peptides.2014.08.009. Epub 2014 Aug 23.
The nociceptin receptor (NOP) and its ligand nociceptin/orphanin FQ (N/OFQ) have been shown to exert a modulatory effect on immune cells during sepsis. We evaluated the suitability of an experimental lipopolysaccharide (LPS)-induced sepsis model for studying changes in the nociceptin system. C57BL/6 mice BALB/c mice and Wistar rats were inoculated with different doses of LPS with or without a nociceptin receptor antagonist (UFP-101 or SB-612111). In C57BL/6 mice LPS 0.85 mg/kg injection produced no septic response, whereas 1.2mg/kg produced a profound response within 5h. In BALB/c mice, LPS 4 mg/kg produced no response, whereas 7 mg/kg resulted in a profound response within 24h. In Wistar rats LPS 15 mg/kg caused no septic response in 6/10 animals, whereas 25mg/kg resulted in marked lethargy before 24h. Splenic interleukin-1β mRNA in BALB/c mice, and serum TNF-α concentrations in Wistar rats increased after LPS injection in a dose-dependent manner, but were undetectable in control animals, indicating that LPS had stimulated an inflammatory reaction. IL-1β and TNF-α concentrations in LPS-treated animals were unaffected by administration of a NOP antagonist. Similarly NOP antagonists had no effect on survival or expression of mRNA for NOP or ppN/OFQ (the N/OFQ precursor) in a variety of tissues. In these animal models, the dose-response curve for LPS was too steep to allow use in survival studies and no changes in the N/OFQ system occurred within 24h. We conclude that LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis.
伤害感受素受体(NOP)及其配体伤害感受素/孤啡肽FQ(N/OFQ)已被证明在脓毒症期间对免疫细胞发挥调节作用。我们评估了实验性脂多糖(LPS)诱导的脓毒症模型用于研究伤害感受素系统变化的适用性。将C57BL/6小鼠、BALB/c小鼠和Wistar大鼠接种不同剂量的LPS,同时给予或不给予伤害感受素受体拮抗剂(UFP-101或SB-612111)。在C57BL/6小鼠中,注射0.85mg/kg的LPS未产生脓毒症反应,而1.2mg/kg在5小时内产生了强烈反应。在BALB/c小鼠中,4mg/kg的LPS未产生反应,而7mg/kg在24小时内导致了强烈反应。在Wistar大鼠中,15mg/kg的LPS在6/10只动物中未引起脓毒症反应,而25mg/kg在24小时前导致明显嗜睡。LPS注射后,BALB/c小鼠脾脏白细胞介素-1β mRNA和Wistar大鼠血清肿瘤坏死因子-α浓度呈剂量依赖性增加,但在对照动物中未检测到,表明LPS刺激了炎症反应。LPS处理动物中的白细胞介素-1β和肿瘤坏死因子-α浓度不受NOP拮抗剂给药的影响。同样,NOP拮抗剂对多种组织中NOP或ppN/OFQ(N/OFQ前体)的mRNA表达或存活没有影响。在这些动物模型中,LPS的剂量反应曲线过于陡峭,无法用于存活研究,并且在24小时内N/OFQ系统没有发生变化。我们得出结论,在啮齿动物中接种LPS是研究脓毒症中NOP-N/OFQ系统可能变化的不合适模型。