血管生成素1通过ErbB1信号通路调节c-Abl介导大鼠慢性术后痛

Ang-1 Mediates Chronic Postsurgical Pain Through Modulating c-Abl Via ErbB1 Signaling Pathway in Rats

目的:探讨血管生成素-1(Ang-1)、表皮生长因子受体(EGFR/ErbB1)和非受体酪氨酸激酶(c-Abl)在大鼠皮肤肌肉切口牵拉慢性术后痛模型中的作用及机制。方法:将60只大鼠分为对照组、假手术组和模型组,各20只,测定术后1、3、7、14、28d机械性刺激缩爪阈值;选取假手术组和模型组术后第7天进行转录组学测序,检测脊髄中Ang-1、ErbB1和c-Abl表达及定位。结果:和术前比,模型组机械性刺激缩爪阈值(MWT)呈时间依赖性下降;与对照组和假手术组比,模型组各时点MWT降低。模型组术后第7天Ang-1表达降低,ErbB1、c-Abl表达增加,KEGG信号通路分析发现ErbB信号通路,蛋白互作网络分析发现Ang-1、ErbB1和c-Abl存在关联。免疫荧光发现Ang-1与神经元标记物(NeuN)和小胶质细胞标记物(Iba1)共定位,ErbB1与NeuN、GFAP共定位,c-Abl与GFAP、Iba1共定位。结论:Ang-1、ErbB1和c-Abl参与了慢性术后痛(CPSP)的发生发展,Ang-1通过ErbB信号通路调节c-Abl在CPSP中发挥重要作用。

Objective:To investigate the role and mechanism of angiopoietin-1(Ang-1),epidermal growth factor receptor(ErbB1)and non-receptor tyrosine kinase(c-Abl)in chronic postsurgical pain by establishing the model of skin/muscle incision and retraction(SMIR)in rats.Methods:60 rats were divided into normal group(Naive group),sham operations group(Sham group)and SMIR group,20 rats each.Mechanical withdrawal threshold(MWT)was measured at 1,3,7,14,and 28 days after operation.The rats in the Sham group and the SMIR group were selected for transcriptomic sequencing on the 7th day after operation.the expression and localization of Ang-1,ErbB1 and c-Abl in spinal cords were examined.Results:Compared with preoperative,the MWT of the SMIR group decreased in a time-dependent manner.Compared with the Naive and Sham groups,the MWT of the SMIR group decreased at each time point.The expression of Ang-1 decreased,the expression of ErbB1 and c-Abl increased on the 7th day after operation in the SMIR group.KEGG signaling pathway analysis found ErbB signaling pathway,Protein interaction network(PPI)analysis found that Ang-1,ErbB1 and c-Abl were associated.Immunofluorescence staining showed that Ang-1 co-localized with neuronal marker(NeuN)and microglia marker(Iba1),ErbB1 co-localized with NeuN and GFAP,and c-Abl co-localized with GFAP and Iba1.Conclusion:Ang-1 plays an important role in chronic postoperative pain(CPSP)by regulating c-Abl through ErbB signaling pathway,which provides a theoretical basis for the treatment of CPSP.