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      Relationship Between Proteinase with a Disintegrin and a Metalloproteinase Domain-9 (ADAM9), Inflammation, Airway Remodeling, and Emphysema in COPD Patients

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          Background and Objective

          The link between ADAM9 and airway remodeling and emphysema severity in COPD patients has not been elucidated. Here, we investigated the relationship between ADAM9 levels in sputum and airway epithelium and the clinical characteristics of COPD patients.


          A sputum cohort and a lung tissue cohort were included in the study. Pulmonary function and computed tomography data were analyzed in COPD patients, non-COPD smokers, and non-smokers. Soluble ADAM9 and interleukin 8 (IL-8) levels in sputum supernatants as well as surface ADAM9 expression in airway epithelium were detected. Emphysema scores were calculated by the percentage of low attenuation area (%LAA-950), and airway remodeling was measured via airway thickening and loss of airway counts.


          Both soluble ADAM9 levels in sputum and relative surface ADAM9 expression in airway epithelium were increased in COPD patients. Sputum ADAM9 levels were negatively correlated with forced expiratory volume in 1 s of predicted (FEV1% of predicted) and positively correlated with sputum IL-8 levels, but not with CT measured emphysema nor airway remodeling. The ADAM9 expression in airway epithelia was positively correlated with %LAA-950 and airway wall thickening parameters (wall area percentage, WA%; the square root of the wall area in a standard airway with a 10 mm internal perimeter, Pi-10), while negatively correlated with airway counts derived from the 4th to 9th bronchial generations.


          Airway ADAM9 levels in sputum and airway epithelium were both elevated in COPD patients compared to non-COPD controls. Sputum ADAM9 seemed to be associated with inflammatory responses in COPD, while epithelial ADAM9 was more correlated with emphysema and airway remodeling.

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          Most cited references 33

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          Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

          The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.
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            Series "matrix metalloproteinases in lung health and disease": Matrix metalloproteinases in COPD.

            There is considerable evidence that matrix metalloproteinases (MMPs) are up- and/or downregulated in chronic obstructive pulmonary disease (COPD), particularly in emphysema, in which they probably participate in proteolytic attack on the alveolar wall matrix. Recent data suggest that MMPs also have major roles in driving inflammation or shutting it down, as well as modifying the release of fibrogenic growth factors, processes that are important in the genesis of the various lesions of COPD. In cigarette smoke-induced animal models of emphysema, MMP-12 appears to play a consistent and important role, whereas the data for other MMPs are difficult to interpret. In human lungs, evidence for a role for MMPs is more tenuous and there are numerous contradictions in the literature. Little is known about the effects of MMPs in small airway remodelling, smoke-induced pulmonary hypertension and chronic bronchitis, but MMP-12 participates in experimental small airway modelling. To date, the accumulated data suggest that selective inhibition of MMP-12 might be a viable therapy for emphysema and small airway remodelling, but subtle differences in the functions of MMP-12 in animals and humans mandate caution with this approach. Whether inhibition of other MMPs might be useful is unclear.
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              Architecture of the human lung. Use of quantitative methods establishes fundamental relations between size and number of lung structures.

              An attempt has been made to define quantitatively the architecture of airways and blood vessels of the human lung. For this purpose five normal lungs from individuals aged 8 to 74 years were subjected to a dimensional analysis by several methods of measurement based on statistical principles. The elements of the "respiratory zone" may be regarded as randomly distributed in the lung. There are essentially the same number of alveoli (300 million), alveolar ducts (14 million), and capillary segments (280 billion) in all lungs. The dimensions of these architectural elements are shown to depend mainly on the size of the lung. The effect on these dimensions of such functional variables as the degree of inflation of the lung or of the filling of capillaries with blood are discussed. The alveolar and alveolar-capillary surface areas, which are of importance in the analysis of gas exchange between air and blood, are found to increase with the size of the lung. In our material, both varied in the range of 40 to 80 square meters. The elements of the conductive zone of the lung show a polar orientation. The airways have, on the average, 23 generations of dichotomous branching; the pulmonary arteries reach the precapillaries after about 28 generations. The average diameters of the airway and blood-vessel elements at each generation appear to follow the laws of "best" dimensions. The functional significance of this finding is discussed. It is suggested that morphometric studies conducted according to this general model may be useful in the anatomical description of other organs (16).

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                14 December 2020
                : 15
                : 3335-3346
                [1 ]Department of Pulmonary Medicine, Qilu Hospital, Shandong University , Jinan, People’s Republic of China
                [2 ]Department of Cadre Health Care, Qilu Hospital, Shandong University , Jinan, People’s Republic of China
                [3 ]Department of Pulmonary Medicine, Linyi People’s Hospital , Linyi, People’s Republic of China
                Author notes
                Correspondence: Wei Xiao Department of Pulmonary Medicine, Qilu Hospital, Shandong University , 107 Wenhuaxi Road, Jinan250012, People’s Republic of China Email
                © 2020 Cui 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: 15, References: 34, Pages: 12
                Funded by: the National Key Research and Development Program in China;
                This study was supported by grants from the National Key Research and Development Program in China (2016YFC0903603). The funding body has no role in study design, data collection, analysis, and interpretation, and in writing the manuscript.
                Original Research


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