Levänen Bettina, Glader Pernilla, Dahlén Barbro, Billing Bo, Qvarfordt Ingemar, Palmberg Lena, Larsson Kjell, Lindén Anders
Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm.
Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg.
Int J Chron Obstruct Pulmon Dis. 2016 Sep 6;11:2109-2116. doi: 10.2147/COPD.S99900. eCollection 2016.
There is excessive accumulation of neutrophils in the airways in chronic obstructive pulmonary disease (COPD) but the underlying mechanisms remain poorly understood. It is known that extracellular cytokine signaling via interleukin (IL)-17A contributes to neutrophil accumulation in the airways but nothing is known about the impact of tobacco smoking on extracellular signaling via IL-17A. Here, we characterized the impact of tobacco smoking on extracellular cytokine signaling via IL-17A in the peripheral airways in long-term smokers with and without COPD and in occasional smokers before and after short-term exposure to tobacco smoke. We quantified concentrations of IL-17A protein in cell-free bronchoalveolar lavage (BAL) fluid samples (Immuno-quantitative PCR) and cytotoxic T-cells (immunoreactivity for CD8 and CD3) in bronchial biopsies. Matrix metalloproteinase-8 and human beta defensin 2 proteins were also quantified (enzyme-linked immunosorbent assay) in the BAL samples. The concentrations of IL-17A in BAL fluid were higher in long-term smokers without COPD compared with nonsmoking healthy controls, whereas those with COPD did not differ significantly from either of the other groups. Short-term exposure to tobacco smoke did not induce sustained alterations in these concentrations in occasional smokers. Long-term smokers displayed higher concentrations of IL-17A than did occasional smokers. Moreover, these concentrations correlated with CD8 and CD3 cells in biopsies among long-term smokers with COPD. In healthy nonsmokers, BAL concentrations of matrix metalloproteinase-8 and IL-17A correlated, whereas this was not the case in the pooled group of long-term smokers with and without COPD. In contrast, BAL concentrations of human beta defensin 2 and IL-17A correlated in all study groups. This study implies that long-term but not short-term exposure to tobacco smoke increases extracellular cytokine signaling via IL-17A in the peripheral airways. In the smokers with COPD, this signaling may involve cytotoxic T-cells. Long-term exposure to tobacco smoke leads to a disturbed association of extracellular IL-17A signaling and matrix metalloproteinase-8, of potential importance for the coordination of antibacterial activity.
在慢性阻塞性肺疾病（COPD）中，气道内存在中性粒细胞的过度积聚，但其潜在机制仍知之甚少。已知细胞外细胞因子通过白细胞介素（IL）-17A信号传导促成气道内中性粒细胞的积聚，但关于吸烟对通过IL-17A进行的细胞外信号传导的影响尚不清楚。在此，我们描述了吸烟对长期吸烟且患有或未患有COPD的患者以及偶尔吸烟者在短期接触烟草烟雾前后外周气道中通过IL-17A进行的细胞外细胞因子信号传导的影响。我们对无细胞支气管肺泡灌洗（BAL）液样本中的IL-17A蛋白浓度（免疫定量PCR）以及支气管活检中的细胞毒性T细胞（CD8和CD3的免疫反应性）进行了定量。还对BAL样本中的基质金属蛋白酶-8和人β防御素2蛋白进行了定量（酶联免疫吸附测定）。与非吸烟健康对照相比，无COPD的长期吸烟者BAL液中IL-17A的浓度更高，而患有COPD的吸烟者与其他两组中的任何一组相比均无显著差异。短期接触烟草烟雾并未在偶尔吸烟者中引起这些浓度的持续变化。长期吸烟者的IL-17A浓度高于偶尔吸烟者。此外，在患有COPD的长期吸烟者中，这些浓度与活检中的CD8和CD3细胞相关。在健康非吸烟者中，BAL中基质金属蛋白酶-8和IL-17A的浓度相关，而在患有和未患有COPD的长期吸烟者合并组中情况并非如此。相反，在所有研究组中，BAL中人β防御素2和IL-17A的浓度相关。这项研究表明，长期而非短期接触烟草烟雾会增加外周气道中通过IL-17A进行的细胞外细胞因子信号传导。在患有COPD的吸烟者中，这种信号传导可能涉及细胞毒性T细胞。长期接触烟草烟雾会导致细胞外IL-17A信号传导与基质金属蛋白酶-8之间的关联紊乱，这对抗菌活性的协调可能具有重要意义。
