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      Increased MMP8 Levels in Atopic Chronic Obstructive Pulmonary Disease: A Study Testing Multiple Immune Factors in Atopic and Non-Atopic Patients

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          The aim of this study was to analyse the level of serum matrix metalloproteinases (MMPs) in atopic and non-atopic COPD patients, providing guidance for clinical practice and theory for atopic COPD.


          Blood samples from 50 adult male patients with COPD, including 17 atopic and 33 non-atopic patients, were submitted for detection of MMP8, MMP9, surfactant associated protein D (SPD), noradrenaline (NE), leukotriene (LT) B4, recombinant proteoglycan (PRG4), Phadiatop sIgE, and tIgE levels. Patients’ Modified Medical Research Council Dyspnea Scale (mMRC), COPD Assessment Test (CAT), pulmonary function test results, FeNO, blood cell ratio and induced sputum were collected.


          The level of serum tIgE in patients with atopic COPD [1876.00 kU/l (760.50, 5347.00)] was significantly higher than in patients with non-atopic COPD [377.00 kU/l (93.50, 581.50), P < 0.001]. The MMP8 levels in atopic COPD (1600 ± 1181 ng/mL) were significantly higher than in non-atopic COPD (973.3 ±921.5 ng/mL, P = 0.0494), but there was no significant difference in MMP9, SPD, NE, LTB4, and PRG4 levels between the two groups. In atopic COPD patients, the rate of leukocyte ( r s = 0.63, P < 0.001) and neutrophil ( r s = 0.54, P < 0.05) were positively correlated with MMP8 levels, while lymphocyte rate was negatively correlated with MMP8 ( r s = −0.70, P < 0.001) and MMP9 levels ( r s = −0.54, P < 0.05). Optimal scale analysis showed that NE was most closely related to the basophil rate from induced sputum and FeNO levels (Cronbach’s alpha = 85.1%). Interestingly, all atopic COPD patients with mMRC ≥2, CAT ≥ 10, and CCQ ≥16 exhibited MMP8 levels >1000 ng/mL.


          In general, tIgE and MMP8 levels were higher in atopic COPD patients than in non-atopic patients. NE levels were closely correlated with the basophil rate of induced sputum and FeNO levels, which may play an important role in the pathogenesis and development of atopic COPD.

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          Most cited references 22

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          Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

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            Matrix metalloproteinases -8, -9 and -12 in smokers and patients with Stage 0 COPD

            COPD is underdiagnosed and its early assessment is problematic. It has been suggested that symptomatic smokers with normal FEV1/FVC (Stage 0 COPD, GOLD criteria) can develop COPD in the future. Potential early biomarkers in COPD include the matrix metallo-proteinases (MMPs). It is not yet known, whether alterations in MMP expression are associated with smoking alone or with the risk of developing COPD. In this cross-sectional study MMP-8, MMP-9 and MMP-12 were determined from induced sputum and plasma by ELISA, immunocytochemistry, zymography, and/or Western blot in non-smokers (n = 32), smokers with symptoms (Stage 0, GOLD criteria) (n = 23) or without symptoms (n = 23). Only MMP-8 differentiated Stage 0 COPD from non-symptomatic smokers (p = 0.02). MMP-9 levels were significantly elevated in the induced sputum of non-symptomatic smokers and Stage 0 COPD (p = 0.01, p < 0.001) compared to non-smokers, but did not differ between the two subgroups of smokers. MMP-12 was higher only at Stage 0 compared to non-smokers (p = 0.04). MMP-8, MMP-9 and MMP-12 immunoreactivity was localized in macrophages and neutrophils, especially in smokers. MMP-8 levels correlated significantly with the small airway flow parameters (MEF50, MEF25) (p = 0.005 and p = 0.0004) and markers of neutrophil activation (myeloperoxidase, lactoferrin). In conclusion MMP-8 may differentiate Stage 0 from healthy smokers.
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              Leukotriene B 4 antagonism ameliorates experimental lymphedema

              Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B4 (LTB4). LTB4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB4 was functionally bimodal: Lower LTB4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB4 stimulated, whereas high concentrations of LTB4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1–/– mice were refractory to the beneficial effects of LTB4 antagonism, suggesting that LTB4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB4 is a promising drug target for the treatment of acquired lymphedema.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                30 July 2020
                : 15
                : 1839-1848
                [1 ]Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , Guangzhou 510120, Guangdong, People’s Republic of China
                [2 ]Department of Laboratory Medicine, Shenzhen Institute of Respiratory Diseases, Shenzhen People’s Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University , Shenzhen, Guangdong 518020, People’s Republic of China
                Author notes
                Correspondence: Baoqing Sun First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiangxi Road, Guangzhou 510120, Guangdong, People’s Republic of ChinaTel +86 20 8306 2865Fax +86 20 8306 2729 Email

                These authors contributed equally to this work

                © 2020 Hu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 4, Tables: 4, References: 24, Pages: 10
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: Guangzhou Science and Technology Innovation Committee;
                Funded by: Guangzhou Education Bureau;
                Funded by: State Key Laboratory of Respiratory Disease Foundation;
                This study was supported by National Natural Science Foundation of China (NSFC 81871736); Guangzhou Science and Technology Innovation Committee (201804020043); Guangzhou Education Bureau (201831802); and State Key Laboratory of Respiratory Disease Foundation (SKLRD-MS-201906, SKLRD-OP-201803). The funders had no role in study design, data analysis, preparation of the manuscript, or decision to publish.
                Original Research


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