Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation
Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation
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DOI：
10.1111/j.1365-2222.2007.02851.x
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发表时间：
2007-12-01
影响因子：
6.1
通讯作者：
Fischer, A.
中科院分区：
文献类型：
--
作者：
Springer, J.;Groneberg, D. A.;Fischer, A.
背景 活性氧 (ROS) 的诱导是炎症的特征，但迄今为止，过敏性气道疾病的确切途径尚未确定。 目的 本研究的目的是表征速激肽 NK-1 受体在过敏原激发以及随后的炎症和重塑过程中对 ROS 产生的作用。 方法 精密切割卵清蛋白 (OVA) 致敏的肺切片 培养小鼠并通过2',7'-二氯荧光素-二乙酸酯方法检查响应OVA攻击(10μg/mL)的ROS生成。通过 5-bromo-2'-deoxyuridine 掺入（72 小时）研究 ROS 对上皮增殖的长期影响。在体内，结果在 OVA 致敏动物中得到了验证，这些动物在过敏原攻击前用安慰剂、速激肽神经激肽 1 (NK-1) 受体拮抗剂 SR 140333 或抗氧化剂 N-乙酰半胱氨酸 (NAC) 进行鼻内治疗。过敏原攻击后 48 小时评估炎症浸润和重塑。结果 ROS 生成增加 3.7 倍，这被 SR 140333 抑制。[Sar(9),Met(11)(O-2)]-P 物质 (5nM) 导致速激肽 NK-1 受体依赖性 ROS 生成增加四倍。与 [Sar(9),Met(11)(O-2)]-SP 孵育 72 小时以上，上皮增殖减少 68%。体内，SR 140333 和 NAC 治疗可减少上皮损伤（与安慰剂相比分别为 91.4% 和 76.8%，P < 0.01）和杯状细胞增生（与安慰剂相比分别为 67.4% 和 50.1%，P < 0.05），并减少炎症细胞流入（与安慰剂相比分别为 65.3% 和 45.3%，P < 0.01). 结论 过敏原激发以速激肽 NK-1 受体依赖性方式诱导 ROS。抑制速激肽 NK-1 受体可减少上皮损伤和随后的体内重塑。因此，患者可能会受益于包括自由基清除剂或速激肽 NK-1 受体拮抗剂的治疗方案。
Background An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far.Objective The aim of this study was to characterize the role of the tachykinin NK-1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling.Methods Precision-cut lung slices of ovalbumin (OVA)-sensitized mice were cultivated and ROS-generation in response to OVA challenge (10 mu g/mL) was examined by the 2',7'-dichloroflourescein-diacetate method. Long-term ROS effects on epithelial proliferation were investigated by 5-bromo-2'-deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA-sensitized animals which were treated intra-nasally with either placebo, the tachykinin neurokinin 1 (NK-1) receptor antagonist SR 140333 or the anti-oxidant N-acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge.Results ROS generation was increased by 3.7-fold, which was inhibited by SR 140333. [Sar(9),Met(11)(O-2)]-Substance P (5nM) caused a tachykinin NK-1 receptor-dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar(9),Met(11)(O-2)]-SP over 72 h. In-vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P < 0.01) and goblet cell hyperplasia (67.4% and 50.1% vs. placebo, respectively, P < 0.05), and decreased inflammatory cell influx (65.3% and 45.3% vs. placebo, respectively, P < 0.01).Conclusion Allergen challenge induces ROS in a tachykinin NK-1 receptor-dependent manner. Inhibition of the tachykinin NK-1 receptor reduces epithelial damage and subsequent remodelling in vivo. Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK-1 receptor antagonists.