Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England; Department of Laboratory Medicine, Dokkyo Medical University Koshigaya Hospital, Minami-Koshigaya Koshigaya-City Saitama, Japan.
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England.
Chest. 2013 Aug;144(2):515-521. doi: 10.1378/chest.12-2381.
Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of fibrinolysis at sites of vascular injury and thrombus formation. Recently, sputum PAI-1 was reported to be elevated in COPD. However, the mechanism of PAI-1 elevation in COPD has yet to be clarified. Here, we show that PAI-1 elevation in COPD is closely associated with oxidative stress-induced nuclear factor κB (NF-κB) activation.
Patients and control subjects were recruited from the outpatient department of Royal Brompton Hospital, local general practice, and the National Heart and Lung Institute. Sputum samples were obtained, and sputum sample processing was performed to obtain sputum supernatants and sputum macrophages.
The mean PAI-1 level in COPD sputum (1.92 ± 3.11 ng/mL, n = 32) was higher than that of both age-matched smokers without COPD (0.48 ± 0.63 ng/mL, n = 11) and healthy nonsmokers (0.55 ± 1.11 ng/mL, n = 9). Sputum PAI-1 significantly correlated with sputum malondialdehyde (MDA) in COPD (r = 0.59, P < .001). In addition, NF-κB activity in sputum macrophages (three control and seven COPD subjects) significantly correlated with both sputum PAI-1 (r = 0.72, P < .05) and sputum MDA (r = 0.78, P < .01). An in vitro study showed that both hydrogen peroxide and cigarette smoke-conditioned medium induced PAI-1 production in A549 cells, and the production was inhibited by an inhibitor of I κB kinase-β in a concentration-dependent manner. Furthermore, histone deacetylase 2 (HDAC2) knockdown by RNA interference, a mimic of oxidative-stress-dependent HDAC2 reduction, enhanced tumor necrosis factor-α-induced PAI-1 induction (half maximal effective concentration [EC50], 0.64 ± 0.19 ng/mL in HDAC2-KD, 7.64 ± 3.70 ng/mL in control) concomitant with enhancement of NF-κB p65 acetylation and NF-κB DNA-binding activity.
Oxidative stress, directly or indirectly via HDAC reduction, plays a role in PAI-1 expression in COPD via activation of NF- κ B.
纤溶酶原激活物抑制剂-1（PAI-1）是血管损伤和血栓形成部位纤维蛋白溶解的重要调节剂。最近，有人报道 COPD 患者的痰 PAI-1 升高。然而，COPD 中 PAI-1 升高的机制尚未阐明。在这里，我们表明 COPD 中 PAI-1 的升高与氧化应激诱导的核因子 κB（NF-κB）激活密切相关。
从皇家布朗普顿医院的门诊部、当地的普通科医生和国家心肺研究所招募患者和对照受试者。获取痰样本，并进行痰样本处理以获得痰上清液和痰巨噬细胞。
COPD 患者的痰 PAI-1 水平（1.92±3.11ng/ml，n=32）高于年龄匹配的无 COPD 吸烟者（0.48±0.63ng/ml，n=11）和健康非吸烟者（0.55±1.11ng/ml，n=9）。COPD 患者的痰 PAI-1 与痰丙二醛（MDA）显著相关（r=0.59，P<0.001）。此外，痰巨噬细胞中的 NF-κB 活性（3 名对照和 7 名 COPD 受试者）与痰 PAI-1（r=0.72，P<0.05）和痰 MDA（r=0.78，P<0.01）均显著相关。体外研究表明，过氧化氢和香烟烟雾条件培养基均可诱导 A549 细胞产生 PAI-1，并且该产生可被 IκB 激酶-β抑制剂以浓度依赖性方式抑制。此外，通过 RNA 干扰敲低组蛋白去乙酰化酶 2（HDAC2），一种氧化应激依赖性 HDAC2 减少的模拟物，增强肿瘤坏死因子-α诱导的 PAI-1 诱导（半最大有效浓度[EC50]，HDAC2-KD 为 0.64±0.19ng/ml，对照为 7.64±3.70ng/ml），同时增强 NF-κB p65 乙酰化和 NF-κB DNA 结合活性。
氧化应激通过激活 NF- κ B 直接或间接通过 HDAC 减少在 COPD 中发挥作用，从而影响 PAI-1 的表达。
