Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
J Cyst Fibros. 2019 Mar;18(2):203-211. doi: 10.1016/j.jcf.2018.06.001. Epub 2018 Jun 28.
Cystic fibrosis (CF) lung disease is characterized by aggressive neutrophil-dominated inflammation mediated in large part by neutrophil elastase (NE), an omnivorous protease released by activated or disintegrating neutrophils and a key therapeutic target. To date, several short-term studies have shown that anti-NE compounds can inhibit NE and have anti-inflammatory effects. However, progression to large-scale or multicenter clinical trials has been hampered by the fact that the current gold standard methodology of evaluating airway NE inhibition, bronchoalveolar lavage (BAL), is invasive, difficult to standardize across sites and excludes those with severe lung disease. Attempts to utilize sputum that is either spontaneously expectorated (SS) or induced (IS) have been hindered by poor reproducibility, often due to the various processing methods employed. In this study, we evaluate TEmperature-controlled Two-step Rapid Isolation of Sputum (TETRIS), a specialized method for the acquisition and processing of SS and IS. Using TETRIS, we show for the first time that NE activity and cytokine levels are comparable in BAL, SS and IS samples taken from the same people with CF (PWCF) on the same day once this protocol is used. We correlate biomarkers in TETRIS-processed IS and clinical outcome measures including FEV, and show stability and reproducible inhibition of NE over time in IS processed by TETRIS. The data offer a tremendous opportunity to evaluate prognosis and therapeutic interventions in CF and to study the full spectrum of people with PWCF, many of whom have been excluded from previous studies due to being unfit for BAL or unable to expectorate sputum.
囊性纤维化（CF）肺病的特征是侵袭性中性粒细胞为主的炎症，主要由中性粒细胞弹性蛋白酶（NE）介导，NE 是一种由活化或崩解的中性粒细胞释放的兼性噬菌蛋白酶，也是一个关键的治疗靶点。迄今为止，几项短期研究表明，抗 NE 化合物可以抑制 NE 并具有抗炎作用。然而，由于评估气道 NE 抑制的当前金标准方法支气管肺泡灌洗（BAL）具有侵入性、难以在各部位标准化以及排除了那些患有严重肺部疾病的患者，因此该方法难以推进到大规模或多中心临床试验。试图利用自发咳出（SS）或诱导（IS）的痰液一直受到限制，其原因通常是所采用的各种处理方法的重复性较差。在这项研究中，我们评估了 TEmperature-controlled Two-step Rapid Isolation of Sputum（TETRIS），这是一种专门用于获取和处理 SS 和 IS 的方法。使用 TETRIS，我们首次表明，在同一天从同一 CF 患者（PWCF）采集的 BAL、SS 和 IS 样本中，NE 活性和细胞因子水平具有可比性，一旦使用了该方案。我们将 TETRIS 处理的 IS 中的生物标志物与包括 FEV 在内的临床结果测量进行了关联，并显示了 TETRIS 处理的 IS 中 NE 随时间的稳定性和可重复性抑制。这些数据为评估 CF 的预后和治疗干预提供了巨大机会，并研究了 PWCF 人群的全貌，其中许多人由于不适合 BAL 或无法咳出痰液而被排除在之前的研究之外。
