Ijpma Gijs, Kachmar Linda, Panariti Alice, Matusovsky Oleg S, Torgerson Dara, Benedetti Andrea, Lauzon Anne-Marie
Dept of Medicine, McGill University, Montreal, QC, Canada.
Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Eur Respir J. 2020 Jul 2;56(1). doi: 10.1183/13993003.02178-2019. Print 2020 Jul.
Constriction of airways during asthmatic exacerbation is the result of airway smooth muscle (ASM) contraction. Although it is generally accepted that ASM is hypercontractile in asthma, this has not been unambiguously demonstrated. Whether airway hyperresponsiveness (AHR) is the result of increased ASM mass alone or also increased contractile force generation per unit of muscle directly determines the potential avenues for treatment.To assess whether ASM is hypercontractile we performed a series of mechanics measurements on isolated ASM from intrapulmonary airways and trachealis from human lungs. We analysed the ASM and whole airway proteomes to verify if proteomic shifts contribute to changes in ASM properties.We report an increase in isolated ASM contractile stress and stiffness specific to asthmatic human intrapulmonary bronchi, the site of increased airway resistance in asthma. Other contractile parameters were not altered. Principal component analysis (PCA) of unbiased mass spectrometry data showed clear clustering of asthmatic subjects with respect to ASM specific proteins. The whole airway proteome showed upregulation of structural proteins. We did not find any evidence for a difference in the regulation of myosin activity in the asthmatic ASM.In conclusion, we showed that ASM is indeed hyperreactive at the level of intrapulmonary airways in asthma. We identified several proteins that are upregulated in asthma that could contribute to hyperreactivity. Our data also suggest enhanced force transmission associated with enrichment of structural proteins in the whole airway. These findings may lead to novel directions for treatment development in asthma.
哮喘急性加重期气道收缩是气道平滑肌（ASM）收缩的结果。尽管人们普遍认为哮喘患者的ASM具有高收缩性，但这一点尚未得到明确证实。气道高反应性（AHR）仅仅是ASM质量增加的结果，还是每单位肌肉产生收缩力的增加，直接决定了潜在的治疗途径。为了评估ASM是否具有高收缩性，我们对来自人肺肺内气道和气管的分离ASM进行了一系列力学测量。我们分析了ASM和整个气道的蛋白质组，以验证蛋白质组的变化是否有助于ASM特性的改变。我们报告了哮喘患者肺内支气管特异性分离ASM收缩应力和硬度的增加，肺内支气管是哮喘气道阻力增加的部位。其他收缩参数未改变。对无偏质谱数据进行主成分分析（PCA）显示，哮喘患者在ASM特异性蛋白方面有明显聚类。整个气道蛋白质组显示结构蛋白上调。我们没有发现哮喘ASM中肌球蛋白活性调节存在差异的任何证据。总之，我们表明哮喘患者肺内气道水平的ASM确实具有高反应性。我们鉴定了几种在哮喘中上调的蛋白质，它们可能导致高反应性。我们的数据还表明，与整个气道结构蛋白富集相关的力传递增强。这些发现可能为哮喘治疗的新方向提供线索。
