Southworth Thomas, Mason Sarah, Bell Alan, Ramis Isabel, Calbet Marta, Domenech Anna, Prats Neus, Miralpeix Montserrat, Singh Dave
1Division of Infection, Immunity & Respiratory Medicine, The Medicines Evaluation Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
3The University of Manchester, 2nd Floor Education and Research Center, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT UK.
Biomark Res. 2018 Apr 11;6:14. doi: 10.1186/s40364-018-0128-9. eCollection 2018.
Inhaled allergen challenges are often used to evaluate novel asthma treatments in early phase clinical trials. Current novel therapeutic targets in asthma include phosphoinositide 3-kinases (PI3K) delta and gamma, p38 mitogen-activated protein kinase (p38) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathways. The activation of these pathways following allergen exposure in atopic asthma patients it is not known.
We collected bronchial biopsies from 11 atopic asthma patients at baseline and after allergen challenge to investigate biomarkers of PI3K, p38 MAPK and JAK/STAT activation by immunohistochemistry. Cell counts and levels of eosinophil cationic protein and interleukin-5 were also assessed in sputum and bronchoalvelar lavage.
Biopsies collected post-allergen had an increased percentage of epithelial cells expressing phospho-p38 (17.5 vs 25.6%, = 0.04), and increased numbers of sub-epithelial cells expressing phospho-STAT5 (122.2 vs 540.6 cells/mm, = 0.01) and the PI3K marker phospho-ribosomal protein S6 (180.7 vs 777.3 cells/mm = 0.005). Type 2 inflammation was increased in the airways post allergen, with elevated levels of eosinophils, interleukin-5 and eosinophil cationic protein.
Future clinical trials of novel kinase inhibitors could use the allergen challenge model in proof of concept studies, while employing these biomarkers to investigate pharmacological inhibition in the lungs.
在早期临床试验中，吸入性过敏原激发试验常被用于评估新型哮喘治疗方法。目前哮喘的新型治疗靶点包括磷酸肌醇3激酶（PI3K）δ和γ、p38丝裂原活化蛋白激酶（p38）以及Janus激酶/信号转导子和转录激活子（JAK/STAT）信号通路。尚不清楚特应性哮喘患者在接触过敏原后这些通路是否会被激活。
我们收集了11例特应性哮喘患者在基线期和过敏原激发试验后的支气管活检样本，通过免疫组织化学研究PI3K、p38丝裂原活化蛋白激酶和JAK/STAT激活的生物标志物。还对痰液和支气管肺泡灌洗中的细胞计数以及嗜酸性粒细胞阳离子蛋白和白细胞介素-5水平进行了评估。
过敏原激发试验后采集的活检样本中，表达磷酸化p38的上皮细胞百分比增加（17.5%对25.6%，P = 0.04），表达磷酸化STAT5的上皮下细胞数量增加（122.2个对540.6个细胞/mm，P = 0.01），PI3K标志物磷酸化核糖体蛋白S6的细胞数量增加（180.7个对777.3个细胞/mm，P = 0.005）。过敏原激发试验后气道中的2型炎症增加，嗜酸性粒细胞、白细胞介素-5和嗜酸性粒细胞阳离子蛋白水平升高。
未来新型激酶抑制剂的临床试验可在概念验证研究中使用过敏原激发试验模型，同时利用这些生物标志物研究肺部的药理抑制作用。
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