神经降压素对内毒素诱导的急性肺损伤的保护作用及机制

目的探讨神经降压素在内毒素（LPS）所诱导的小鼠急性肺损伤（ALI）中的保护作用，并明确其在炎症反应中的作用。 方法100只健康无特异病原级性C57BL/6小鼠（雄性50只，雌性50只），体质量（20~25 g），由上海南方模式实验动物中心提供。所有小鼠随机分为以下5组：①正常对照组：60 μl无菌磷酸缓冲盐溶液（PBS）滴鼻处理小鼠；②急性肺损伤模型组：60 μg/只LPS滴鼻处理；③20 mg/kg神经降压素组：先使用LPS诱导肺损伤，诱导后1 h通过尾静脉注射的方式给予20 mg/kg神经降压素处理；④40 mg/kg神经降压素给药组：先使用LPS诱导肺损伤，诱导后1 h通过尾静脉注射的方式给予40 mg/kg神经降压素处理；⑤80 mg/kg神经降压素给药组：先使用LPS诱导肺损伤，诱导后1 h通过尾静脉注射的方式给予80 mg/kg神经降压素处理。每组20只。肺损伤诱导后24 h，检测不同处理组小鼠肺损伤程度、髓过氧化物酶（MPO）活性、炎症细胞的浸润、肺水肿程度以及肺泡灌洗液中促炎症细胞的分泌水平。 结果与正常对照组相比，LPS的滴鼻处理显著提高了小鼠肺组织的损伤程度，包括MPO活性、炎症细胞的浸润、肺泡灌洗液内促炎症细胞因子［肿瘤坏死因子（TNF-α）、白介素（IL）-6、IL-1b以及单核细胞趋化因子（MCP）-1］的分泌等（P<0.05）；与内毒素诱导的急性肺损伤模型组相比，神经降压素的给药处理明显减轻了小鼠肺组织损伤的程度，包括MPO活性、炎症细胞的浸润、肺泡灌洗液内促炎症细胞因子（TNF-α、IL-6、IL-1b以及MCP-1）的分泌等（P<0.05），且这种保护性作用呈现剂量依赖性。 结论神经降压素能够有效减轻由内毒素诱导的ALI，其机制可能是通过封闭由速激肽所介导的炎症反应信号通路，进而减轻内毒素引起的炎症反应对肺组织所造成的炎症损伤来实现。

Protective effect of neurotensins and its mechanism in LPS-induced acute lung injury

ObjectiveTo investigate the protective effect of neurotensins on inflammatory responses in mice with LPS-induced acute lung injury. Methods100 specific-pathogen free C57BL/6 mice (20-25 g, 6-8 weeks, 50 males and 50 females) were obtained from the Shanghai Laboratory Animal Center (SLAC) (Shanghai, China). All animals were randomly divided into five groups:① Normal control group: mice were treated with 60 μl PBS intratracheally;② LPS-induced acute lung injury group: mice were treated with 60 μg LPS intratracheally;③ 20 mg/kg neurotensins treated ALI group: mice were subjected to LPS-induced ALI and treated with 20 mg/kg Nts via tail vein injection 1 hour after LPS challenge;④ 40 mg/kg neurotensins treated ALI group: mice were subjected to LPS-induced ALI and treated with 40 mg/kg Nts via tail vein injection 1 hour after LPS challenge;⑤ 80 mg/kg neurotensins treated ALI group: mice were subjected to LPS-induced ALI and received 80 mg/kg Nts treatment via tail vein injection. The severity of lung injury, MPO acitvity, neutrophils infilatration, lung edema, and pro-inflammatory cytokines concentration in BALF were assessed 24 hours after ALI. ResultsCompared with the control group of mice, LPS induction significantly increased the severity of lung injury, including the lung edema, inflammatory cell infiltration, and the production of inflammatory cytokines in BALF (TNF-α, IL-6, IL-1β, and MCP-1). However, Neurotensins treatment obviously attenuated the lung injury caused by LPS induction, including the lung edema, the infiltration of inflammatory cells , and the secretion of inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1). Meanwhile, the protective effect is dosage dependent. ConclusionNeurotensins have a protective effect on LPS-induced acute lung injury in mice, and the protective mechanisms may be related to block the tachykinins mediated inflammatory pathways activation.