Division of Pediatric Pneumology and Allergology, University of Lübeck, Lübeck, Germany.
Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Luebeck, Germany.
Clin Exp Allergy. 2018 Nov;48(11):1483-1493. doi: 10.1111/cea.13236. Epub 2018 Aug 28.
Asthma is a chronic inflammatory disease with structural changes present. Burgess and colleagues recently found tumstatin markedly reduced in adult asthmatic lung tissue compared with nonasthmatics. ECM fragments such as tumstatin are named matrikines and act independently of the parent molecule. The role of Col IV matrikines in neutrophil inflammation (eg. exacerbation in asthma) has not been investigated to date. Severe adult asthma phenotypes are dominated by neutrophilic inflammation and show a high frequency of severe exacerbations.
This study sought to investigate the role of a novel active region within tumstatin (CP17) and its implication in neutrophil inflammatory responses related to asthma exacerbation.
For reactive oxygen production, isolated neutrophils were preincubated with peptides or vehicle for 1 hour and stimulated (PMA). Luminescence signal was recorded (integration over 10 seconds) for 1.5 hours. Neutrophil migration was performed according to the SiMA protocol. Mice were sensitized to OVA/Alumn by intraperitoneal (i.p.) injections. Mice were then treated with CP17, vehicle (PBS) or scrambled peptide (SP17) after OVA exposure (days 27 and 28, polyI:C stimulation). All animals were killed on day 29 with lung function measurement, histology and lavage.
CP17 decreased total ROS production rate to 52.44% (0.5 μmol/L, P < 0.05 vs SP17), reduced the in vitro directionality (vs SP17, P = 1 × 10 ) and migration speed (5 μmol/L, P = 1 × 10 ). In vivo application of CP17 decreased neutrophil inflammation ~1.8-fold (P < 0.001 vs SP17) and reduced numbers of mucus-producing cells (-29%, P < 0.05).
CP17 reduced the ROS production rate, migrational speed and selectively inhibited neutrophil accumulation in the lung interstitium and lumen.
CP17 may serve as a potential precursor for drug development to combat overwhelming neutrophil inflammation.
哮喘是一种伴有结构改变的慢性炎症性疾病。Burgess 及其同事最近发现，与非哮喘患者相比，成年哮喘患者的肺组织中 tumstatin 明显减少。ECM 片段（如 tumstatin）被称为基质小肽，其作用独立于母体分子。迄今为止，尚未研究 Col IV 基质小肽在中性粒细胞炎症（例如哮喘恶化）中的作用。严重的成人哮喘表型以中性粒细胞炎症为主，且频繁发生严重恶化。
本研究旨在探讨 tumstatin （CP17）中一个新的活性区域的作用及其与哮喘恶化相关的中性粒细胞炎症反应的关系。
对于活性氧的产生，分离的中性粒细胞用肽或载体孵育 1 小时，然后用 PMA 刺激。记录 1.5 小时内的发光信号（积分 10 秒）。根据 SiMA 方案进行中性粒细胞迁移。用 OVA/Alumn 通过腹腔内（i.p.）注射使小鼠致敏。OVA 暴露后（第 27 和 28 天，聚肌苷酸刺激），用 CP17、载体（PBS）或随机肽（SP17）处理所有小鼠。所有动物于第 29 天处死，进行肺功能测量、组织学和灌洗。
CP17 将总 ROS 产生率降低至 52.44%（0.5 μmol/L，与 SP17 相比，P < 0.05），降低了体外方向性（与 SP17 相比，P = 1 × 10 ）和迁移速度（5 μmol/L，P = 1 × 10 ）。体内应用 CP17 使中性粒细胞炎症减少约 1.8 倍（与 SP17 相比，P < 0.001），并减少黏液产生细胞的数量（-29%，P < 0.05）。
CP17 降低了 ROS 产生率、迁移速度，并选择性抑制了中性粒细胞在肺间质和管腔中的积聚。
CP17 可作为开发药物的潜在前体，以对抗过度的中性粒细胞炎症。
