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Kinetics of TH2 biomarkers in sputum of asthmatics following inhaled allergen

机译：吸入过敏原后哮喘患者痰液中TH2生物标志物的动力学

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BackgroundAllergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum.ObjectivesTo test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints.MethodsThirteen allergic asthmatics with dual allergen-induced airway responses, documented during a single-blind placebo run-in period, participated in a double-blind, two-period crossover study. Each period consisted of three consecutive days, separated by ≥3 weeks. Following randomization, subjects inhaled FP (500 μg bid, five doses total) or placebo. On Day 2 in each study period, allergen challenge was performed and airway response measured by forced expiratory volume in 1 sec (FEV1) until 7 h post-challenge. Sputum was induced 24 h pre-allergen and 7 and 24 h post-allergen. Sputum samples were split into two portions: TH2 biomarkers were quantified by Meso Scale multiplex platform following ultracentrifugation, and cell differentials were counted on Giemsa–May-Grünwald-stained cytospins. Allergen-induced changes in inflammatory endpoints were compared between FP and placebo using a mixed model ANCOVA.ResultsInhaled allergen induced dual airway responses in all subjects during both placebo periods with reproducible late asthmatic response (LAR) and increased sputum inflammatory biomarkers (IL-2, IL-4, IL-13, and eotaxin-1) and eosinophil counts. FP effectively blunted both the LAR and the inflammatory biomarkers.ConclusionsCombining novel, sensitive quantification methods with ultracentrifugation allows reproducible quantification of sputum biomarkers following allergen challenge, reversed by FP. This approach allows non-invasive identification of pharmacodynamic targets for anti-asthma therapies.
机译：背景变应原诱导的晚期气道反应提供了重要的药效学靶标，包括T辅助2（TH2）生物标志物。然而，在二硫苏糖醇处理过的痰中检测炎症标志物受到限制。在单盲安慰剂磨合期间记录的具有双变应原诱导的气道反应的患者参加了双盲，两期交叉研究。每个时期包括连续三天，相隔≥3周。随机分组后，受试者吸入FP（500μgbid，共五剂）或安慰剂。在每个研究阶段的第2天，进行过敏原攻击，并在攻击后7小时内通过1秒内的呼气量（FEV1）来测量气道反应。痰在过敏原前24小时以及过敏原后7和24小时被诱导。痰液样本分为两部分：超速离心后，通过Meso Scale多重平台对TH2生物标志物进行定量，并在Giemsa–May-Grünwald染色的细胞纺锤体上计数细胞差异。结果使用混合模型ANCOVA比较了FP和安慰剂之间变应原诱导的炎症终点变化。结果在两个安慰剂时期，所有受试者吸入的变应原诱导的双重气道反应具有可再现的晚期哮喘反应（LAR）和痰中炎症生物标记物（IL-2 IL-4，IL-13和eotaxin-1）和嗜酸性粒细胞计数。 FP有效地抑制了LAR和炎症生物标志物。结论将新颖，灵敏的定量方法与超速离心相结合，可在过敏原激发后对痰液生物标志物进行可重复的定量，并被FP逆转。这种方法可以非侵入性地确定抗哮喘疗法的药效学靶标。

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