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      Plasma Cathepsin S and Cathepsin S/Cystatin C Ratios Are Potential Biomarkers for COPD

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          Abstract

          Purpose. This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD. Patients and Methods. We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction (“at risk”; AR). In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA. Data were analyzed using simple and logistic regression and receiver operating characteristic analyses. Results. Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups ( p < 0.01). Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation (% FEV 1 predicted < 50%; p = 0.005) and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans (LAA ≥ 8.0; p = 0.001). Conclusion. Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD.

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          Most cited references29

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          Immunologic aspects of chronic obstructive pulmonary disease.

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            Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.

            Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH(2)-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.
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              Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema.

              Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP- and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma.
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                Author and article information

                Journal
                Dis Markers
                Dis. Markers
                DM
                Disease Markers
                Hindawi Publishing Corporation
                0278-0240
                1875-8630
                2016
                22 November 2016
                : 2016
                : 4093870
                Affiliations
                1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
                2Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
                3Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
                4Center for General Internal Medicine and Education, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
                5Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa 259-1193, Japan
                Author notes

                Academic Editor: Massimiliano M. Corsi Romanelli

                Author information
                http://orcid.org/0000-0001-7434-9764
                Article
                10.1155/2016/4093870
                5138488
                27994288
                ec9813cf-67e5-423f-b7b2-8e409425fd2b
                Copyright © 2016 Takahiro Nakajima et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 August 2016
                : 17 October 2016
                Funding
                Funded by: Ministry of Health, Labour and Welfare of Japan
                Funded by: KAKENHI
                Award ID: 14770277
                Categories
                Research Article

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