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Original Research: COPD |

Sputum Plasminogen Activator Inhibitor-1 Elevation by Oxidative Stress-Dependent Nuclear Factor-κB Activation in COPDPlasminogen Activator Inhibitor-1 Elevation in COPD

Masako To, MD, PhD; Dai Takagi, MD, PhD; Kenichi Akashi, MD, PhD; Ichino Kano, LLM; Kosuke Haruki, MD, PhD, MTropMed; Peter J. Barnes, DM, DSc; Kazuhiro Ito, DVM, PhD
Author and Funding Information

From the Airway Disease Section (Drs To, Takagi, Akashi, Barnes, and Ito), National Heart and Lung Institute, Imperial College, London, England; and the Department of Laboratory Medicine (Drs To and Haruki and Ms Kano), Dokkyo Medical University Koshigaya Hospital, Minami-Koshigaya Koshigaya-City Saitama, Japan.

Correspondence to: Kazuhiro Ito, DVM, PhD, Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse St, London, SW3 6LY, England; e-mail: k.ito@imperial.ac.uk


Some of the data included in this study were presented at the American Thoracic Society International Conference, May 13-18, 2011, Denver, Colorado, and the European Respiratory Society Annual Congress, September 1-5, 2012, Vienna, Austria.

Funding/Support: This study was supported by Wellcome Trust and Dokkyo Medical University, Tochigi, Japan.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(2):515-521. doi:10.1378/chest.12-2381
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Background:  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.

Methods:  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.

Results:  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.

Conclusions:  Oxidative stress, directly or indirectly via HDAC reduction, plays a role in PAI-1 expression in COPD via activation of NF- κ B.

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