Infectious Disease Division, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, USA.
Pulmonary, Critical Care and Sleep Division, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, USA.
Thorax. 2014 Sep;69(9):811-8. doi: 10.1136/thoraxjnl-2013-203669. Epub 2014 Mar 31.
Alveolar macrophages (AM) in COPD have fundamentally impaired responsiveness to Toll-like receptor 2 (TLR2) and TLR4 ligands of non-typeable Haemophilus influenzae (NTHI). However, the contribution of innate immune dysfunction to exacerbations of COPD is unexplored. We hypothesised that impaired innate AM responses in COPD extend beyond NTHI to other pathogens and are linked with COPD exacerbations and severity.
AMs, obtained by bronchoalveolar lavage from 88 volunteers with stable-to-moderate COPD, were incubated with respiratory pathogens (NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP) and TLR ligands lipopolysaccharide, Pam3Cys) and elicited IL-8 and TNF-α were measured by microsphere flow cytometry. NF-κB nuclear translocation was measured by colorimetric assay. AM TLR2 and TLR4 expression was determined by immunolabeling and quantitation of mean fluorescent indices. Participants were monitored prospectively for occurrence of COPD exacerbations for 1 year following bronchoscopy. Non-parametric analyses were used to compare exacerbation-prone and non-exacerbation-prone individuals.
29 subjects had at least one exacerbation in the follow-up period (exacerbation-prone) and 59 remained exacerbation-free (non-exacerbation-prone). AMs of exacerbation-prone COPD donors were more refractory to cytokine induction by NTHI (p=0.02), MC (p=0.045) and SP (p=0.046), and to TLR2 (p=0.07) and TLR4 (p=0.028) ligands, and had diminished NF-κB nuclear activation, compared with non-exacerbation-prone counterparts. AMs of exacerbation-prone subjects were more refractory to TLR2 upregulation by MC and SP (p=0.04 each).
Our results support a paradigm of impaired innate responses of COPD AMs to respiratory pathogens, mediated by impaired TLR responses, underlying a propensity for exacerbations in COPD.
慢性阻塞性肺疾病（COPD）患者的肺泡巨噬细胞（AM）对流感嗜血杆菌（NTHI）的 Toll 样受体 2（TLR2）和 TLR4 配体的反应能力基本受损。然而，先天免疫功能障碍对 COPD 恶化的贡献尚未得到探索。我们假设 COPD 患者的固有 AM 反应受损不仅限于 NTHI，还延伸至其他病原体，并与 COPD 恶化和严重程度有关。
通过支气管肺泡灌洗从 88 名稳定至中度 COPD 志愿者中获得 AM，用呼吸道病原体（NTHI、卡他莫拉菌（MC）、肺炎链球菌（SP）和 TLR 配体脂多糖、Pam3Cys）孵育，并通过微球流式细胞术测量白细胞介素-8 和肿瘤坏死因子-α的产生。通过比色测定法测量 NF-κB 核易位。通过免疫标记和平均荧光指数的定量来确定 AM TLR2 和 TLR4 的表达。对支气管镜检查后 1 年的 COPD 恶化情况进行前瞻性监测。使用非参数分析比较易恶化和不易恶化的个体。
29 名受试者在随访期间至少发生一次恶化（易恶化），59 名受试者无恶化（不易恶化）。易恶化 COPD 供体的 AM 对 NTHI（p=0.02）、MC（p=0.045）和 SP（p=0.046）引起的细胞因子诱导、TLR2（p=0.07）和 TLR4（p=0.028）配体的反应性更差，并且 NF-κB 核激活减弱，与不易恶化的对应物相比。易恶化受试者的 AM 对 MC 和 SP 引起的 TLR2 上调的反应性更差（p=0.04 各）。
我们的研究结果支持 COPD AM 对呼吸道病原体的先天反应受损的模式，这是由 TLR 反应受损介导的，这是 COPD 恶化的倾向。
