length Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation
length Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation
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DOI：
10.1016/j.ejphar.2020.173239
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发表时间：
2020-09-05
影响因子：
5
通讯作者：
Prado, Carla M.
中科院分区：
文献类型：
--
作者：
Pinheiro, Nathalia M.;Miranda, Claudia J. C. P.;Prado, Carla M.
在急性炎症模型中，胆碱能抗炎通路主要通过α 7烟碱受体（α 7 nachr）调节肺部炎症和细胞因子释放。我们旨在评估内源性乙酰胆碱在小鼠慢性变应性气道炎症中的作用，以及在该模型中治疗性nAChR刺激的效果。我们首先用65%囊泡性乙酰胆碱转运（VAChT）基因减少（KDVAChT）和野生型（WT）对照对小鼠进行肺部炎症和重塑评估，野生型小鼠皮下致敏，然后吸入卵清蛋白（OVA）。然后，我们评估了PNU282987(0.5 ~ 2mg/kg) （α 7nAChR激动剂）对BALB/c雄性小鼠腹腔致敏，然后用OVA吸入的效果。另一组ova致敏组用PNU-282987加甲基莱卡乌碱（MLA,1 mg/kg， α 7nAChR拮抗剂）治疗，以证实PNU的作用是由α 7nAChR引起的。我们发现，与WT-OVA小鼠相比，KDVAChT-OVA小鼠表现出加重的气道炎症。在BALB/c中，PNU-282987治疗降低了血液、BAL液和气道周围嗜酸性粒细胞的数量，并降低了ova暴露小鼠血清中IL-4、IL-13、IL-17和IgE的水平。MLA预处理消除了PNU-282987的所有作用。此外，我们发现PNU-282987抑制stat3磷酸化并降低SOCS3在肺中的表达。这些数据表明内源性胆碱能张力在小鼠模型中控制变应性气道炎症是重要的。此外，α - 7nAChR可能通过抑制STAT3/SOCS3通路参与嗜酸性粒细胞炎症和气道重塑的控制。综上所述，这些数据表明，以α - 7nAChR为主的胆碱能抗炎系统应进一步考虑作为哮喘的治疗靶点。
The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via alpha 7 nicotinic receptor (alpha 7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU282987(0.5-to-2mg/kg),( alpha 7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, alpha 7nAChR antagonist) to confirm that the effects observed by PNU were due to alpha 7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pretreatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, alpha 7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly alpha 7nAChR should be further considered as a therapeutic target in asthma.