Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD.
Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD.
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DOI：
10.1186/s12890-015-0155-3
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发表时间：
2015-12-07
影响因子：
3.1
通讯作者：
Agustí A
中科院分区：
文献类型：
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作者：
Cosío BG;Jahn A;Iglesias A;Shafiek H;Busquets X;Agustí A
慢性阻塞性肺疾病（COPD）是一种对糖皮质激素部分耐药的炎症性疾病。组蛋白去乙酰化酶（HDAC）活性降低已被提出来解释这种耐药性。流感嗜血杆菌经常定植于COPD患者的气道，在那里它会增强炎症。以前没有研究过流感嗜血杆菌对HDAC活性的影响。研究了存在或不存在流感嗜血杆菌的离体和体外影响。为此，我们测定了：（1）7例COPD患者、5例健康吸烟者、6例健康非吸烟者的肺泡巨噬细胞（AM）中细胞因子的释放;（2）与上皮细胞共培养的巨噬细胞样细胞系（PMA转化的U937细胞）中HDAC活性、核因子κ B（NF-κB B）活化。用地塞米松（1 μM）和/或HDAC增强剂茶碱（10 μM）重复实验。流感嗜血杆菌在COPD和对照组AM中诱导了类固醇抵抗性炎症反应，并降低了HDAC活性，激活了NF-κB，并诱导了巨噬细胞样细胞系中几种细胞因子（IL-6、IL-8、IL-1β、IL-10和TNF-α）的分泌（所有比较p < 0.001）。地塞米松降低NF-κB的活化，但不改变HDAC的活性。在地塞米松中加入茶碱可增加HDAC活性并完全抑制细胞因子释放，而不改变NF-κB活化。这些结果表明，流感嗜血杆菌降低HDAC活性，并诱导NF-κB介导的炎症反应，该炎症反应仅被糖皮质激素部分抑制，而与COPD无关。然而，后者可以通过靶向HDAC活性完全恢复。本文的在线版本（doi：10.1186/s12890-015-0155-3）包含补充材料，可供授权用户使用。
Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before. The effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-κB) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 μM) and/or the HDAC enhancer theophylline (10 μM). Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-κB and induced the secretion of several cytokines (IL-6, IL-8, IL-1β, IL-10 and TNF-α) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-κB activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-κB activation. These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-κB mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity. The online version of this article (doi:10.1186/s12890-015-0155-3) contains supplementary material, which is available to authorized users.