Rimington Tracy L, Hodge Emily, Billington Charlotte K, Bhaker Sangita, K C Binaya, Kilty Iain, Jelinsky Scott, Hall Ian P, Sayers Ian
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Department of Mechanical Engineering, Kathmandu University, Dhulikhel, Nepal.
F1000Res. 2017 Apr 11;6:460. doi: 10.12688/f1000research.10961.1. eCollection 2017.
Airway inflammation is a feature of many respiratory diseases and there is a need for newer, more effective anti-inflammatory compounds. The aim of this study was to develop an human lung explant model which can be used to help study the mechanisms underlying inflammatory responses and which can provide a tool to aid drug discovery for inflammatory respiratory diseases such as asthma and COPD.
Parenchymal lung tissue from 6 individual donors was dissected and cultured with two pro-inflammatory stimuli, lipopolysaccharide (LPS) (1 µg/ml) and interleukin-1 beta (IL-1β) (10 ng/ml) in the presence or absence of dexamethasone (1 µM). Inflammatory responses were assessed using Luminex analysis of tissue culture supernatants to measure levels of 21 chemokines, growth factors and cytokines.
A robust and reproducible inflammatory signal was detected across all donors for 12 of the analytes measured following LPS stimulation with a modest fold increase (<2-fold) in levels of CCL22, IL-4, and IL-2; increases of 2-4-fold in levels of CXCL8, VEGF and IL-6 and increases >4-fold in CCL3, CCL4, GM-CSF, IL-10, TNF-α and IL-1β. The inflammatory signal induced by IL-1β stimulation was less than that observed with LPS but resulted in elevated levels of 7 analytes (CXCL8, CCL3, CCL4, GM-CSF, IL-6, IL-10 and TNF-α). The inflammatory responses induced by both stimulations was supressed by dexamethasone for the majority of analytes.
These data provide proof of concept that this human lung explant model is responsive to inflammatory signals and could be used to investigate the anti-inflammatory effects of existing and novel compounds. In addition this model could be used to help define the mechanisms and pathways involved in development of inflammatory airway disease.
COPD: Chronic Obstructive Pulmonary Disease; ICS: inhaled corticosteroids; LPS: lipopolysaccharide; IL-1β: interleukin-1 beta; PSF: penicillin, streptomycin and fungizone.
气道炎症是许多呼吸系统疾病的一个特征，因此需要更新、更有效的抗炎化合物。本研究的目的是建立一种人肺外植体模型，该模型可用于帮助研究炎症反应的潜在机制，并可为哮喘和慢性阻塞性肺疾病（COPD）等炎症性呼吸系统疾病的药物研发提供工具。
从6名个体供体获取肺实质组织，在存在或不存在地塞米松（1μM）的情况下，用两种促炎刺激物脂多糖（LPS）（1μg/ml）和白细胞介素-1β（IL-1β）（10ng/ml）进行培养。使用Luminex分析组织培养上清液来评估炎症反应，以测量21种趋化因子、生长因子和细胞因子的水平。
在用LPS刺激后，在所有供体中，所测量的12种分析物均检测到强烈且可重复的炎症信号，CCL22、IL-4和IL-2水平有适度的倍数增加（<2倍）；CXCL8、血管内皮生长因子（VEGF）和IL-6水平增加2至4倍，CCL3、CCL4、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IL-10、肿瘤坏死因子-α（TNF-α）和IL-1β水平增加>4倍。IL-1β刺激诱导的炎症信号小于LPS观察到的信号，但导致7种分析物（CXCL8、CCL3、CCL4、GM-CSF、IL-6、IL-10和TNF-α）水平升高。两种刺激诱导的炎症反应在大多数分析物中都被地塞米松抑制。
这些数据提供了概念验证，即这种人肺外植体模型对炎症信号有反应，可用于研究现有和新型化合物的抗炎作用。此外，该模型可用于帮助确定炎症性气道疾病发展中涉及的机制和途径。
COPD：慢性阻塞性肺疾病；ICS：吸入性糖皮质激素；LPS：脂多糖；IL-1β：白细胞介素-1β；PSF：青霉素、链霉素和两性霉素B。
