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      Matrix Metalloproteinases in COPD and atherosclerosis with emphasis on the effects of smoking

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          Abstract

          Background

          Matrix metalloproteinases (MMP´s) are known biomarkers of atherosclerosis. MMP´s are also involved in the pathophysiological processes underlying chronic obstructive pulmonary disease (COPD). Cigarette smoking plays an important role in both disease states and is also known to affect the concentration and activity of MMP´s systemically. Unfortunately, the epidemiological data concerning the value of MMP´s as biomarkers of COPD and atherosclerosis with special regards to smoking habits are limited.

          Methods

          450 middle-aged subjects with records of smoking habits and tobacco consumption were examined with comprehensive spirometry, carotid ultrasound examination and biomarker analysis of MMP-1, -3, -7, -10 and -12. Due to missing data 33 subjects were excluded.

          Results

          The remaining 417 participants were divided into 4 different groups. Group I (n = 157, no plaque and no COPD), group II (n = 136, plaque but no COPD), group III (n = 43, COPD but no plaque) and group IV (n = 81, plaque and COPD). Serum levels of MMP-1,-7,-10-12 were significantly influenced by smoking, and MMP-1, -3, -7 and-12 were elevated in subjects with COPD and carotid plaque. This remained statistically significant for MMP-1 and-12 after adjusting for traditional risk factors.

          Conclusion

          COPD and concomitant plaque in the carotid artery were associated with elevated levels of MMP-1 and -MMP-12 even when adjusting for risk factors. Further studies are needed to elucidate if these two MMP´s could be useful as biomarkers in a clinical setting. Smoking was associated with increased serum levels of MMP´s (except for MMP-3) and should be taken into account when interpreting serum MMP results.

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          Most cited references24

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          How matrix metalloproteinases regulate cell behavior.

          The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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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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              Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair.

              Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) comprise a spectrum of acute inflammatory pulmonary oedema resulting in refractory hypoxaemia in the absence of an underlying cardiogenic cause. There are multiple pulmonary and extrapulmonary causes and ALI/ARDS patients are a clinically heterogeneous group with associated high morbidity and mortality. Inflammatory injury to the alveolar epithelial and endothelial capillary membrane is a central event in the pathogenesis of ALI/ARDS, and involves degradation of the basement membrane. Matrix metalloproteinases (MMPs) have been implicated in a wide variety of pulmonary pathologies and are capable of degrading all components of the extracellular matrix including the basement membrane and key non-matrix mediators of lung injury such as chemokines and cell surface receptors. While many studies implicate MMPs in the injurious process, there are significant gaps in our knowledge of the role of specific proteases at different phases of injury and repair. This article examines the role of MMPs in injury and repair of the alveolar epithelial-endothelial capillary barrier and discusses the potential for MMP modulation in the prevention and treatment of ALI. The need for further mechanistic and in vivo studies to inform appropriate subsequent clinical trials of MMP modulation will be highlighted.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 February 2019
                2019
                : 14
                : 2
                : e0211987
                Affiliations
                [1 ] Clinical Physiology and Nuclear Medicine unit, Department of Translational Medicine, Malmö, Lund University, Malmö, Sweden
                [2 ] Respiratory Medicine and Allergology unit, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
                [3 ] Cardiovascular Epidemiology research group, Department of Clinical Science, Malmö, Lund University, Malmö, Sweden
                National and Kapodistrian University of Athens, GREECE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9289-4766
                Article
                PONE-D-18-33568
                10.1371/journal.pone.0211987
                6383934
                30789935
                6b386a83-295c-4408-9031-b90603041e3c
                © 2019 Kraen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 November 2018
                : 23 January 2019
                Page count
                Figures: 0, Tables: 4, Pages: 10
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100006738, Medicinska Fakulteten, Lunds Universitet;
                Award Recipient :
                Financial support for this study was received from Lund University, Skåne University Hospital and Region Skåne. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Biology and Life Sciences
                Psychology
                Behavior
                Habits
                Smoking Habits
                Social Sciences
                Psychology
                Behavior
                Habits
                Smoking Habits
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Medicine and Health Sciences
                Vascular Medicine
                Atherosclerosis
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Proteases
                Metalloproteases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Proteases
                Metalloproteases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Extracellular Matrix Proteins
                Custom metadata
                The data underlying this study have been deposited to the Swedish National Data Service (SND) and are freely accessible via DOI: 10.5878/eybp-ex91.

                Uncategorized
                Uncategorized

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