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      Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

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          Abstract

          Obstruction of a coronary artery causes ischemia of heart tissue leading to myocardial infarction. Prolonged oxygen deficiency provokes tissue necrosis, which can result in heart failure and death of the patient. Therefore, restoration of coronary blood flow (reperfusion of the ischemic area) by re-canalizing the affected vessel is essential for a better patient outcome. Paradoxically, sudden reperfusion also causes tissue injury, thereby increasing the initial ischemic damage despite restoration of blood flow (=ischemia/reperfusion injury, IRI). Myocardial IRI is a complex event that involves various harmful mechanisms (e.g., production of reactive oxygen species and local increase in calcium ions) as well as inflammatory cells and signals like chemokines and cytokines. An involvement of platelets in the inflammatory reaction associated with IRI was discovered several years ago, but the underlying mechanisms are not yet fully understood. This mini review focusses on platelet contributions to the intricate picture of myocardial IRI. We summarize how upregulation of platelet surface receptors and release of immunomodulatory mediators lead to aggravation of myocardial IRI and subsequent cardiac damage by different mechanisms such as recruitment and activation of immune cells or modification of the cardiac vascular endothelium. In addition, evidence for cardioprotective roles of distinct platelet factors during IRI will be discussed.

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          Most cited references75

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          The inflammatory response in myocardial injury, repair, and remodelling.

          Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.
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            CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.

            CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
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              Neutrophils scan for activated platelets to initiate inflammation.

              Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with an asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream. The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in the redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thromboinflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and they suggest that the neutrophils' bipolarity allows the integration of signals present at both the endothelium and the circulation before inflammation proceeds. Copyright © 2014, American Association for the Advancement of Science.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                06 June 2019
                2019
                : 10
                : 1260
                Affiliations
                Department of Cardiology and Angiology I, Heart Center, University of Freiburg and Faculty of Medicine, University of Freiburg , Freiburg, Germany
                Author notes

                Edited by: Benoît Ho-Tin-Noé, Institut National de la Santé et de la Recherche Médicale (INSERM), France

                Reviewed by: Mark Thomas, University of Birmingham, United Kingdom; Philipp Von Hundelshausen, Ludwig Maximilian University of Munich, Germany

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.01260
                6562336
                31244834
                6573fa58-0648-4a06-8853-7f5302ac2452
                Copyright © 2019 Schanze, Bode and Duerschmied.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 March 2019
                : 17 May 2019
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 87, Pages: 9, Words: 6758
                Categories
                Immunology
                Mini Review

                Immunology
                myocardial infarction,ischemia reperfusion injury,platelets,reperfusion,ischemia
                Immunology
                myocardial infarction, ischemia reperfusion injury, platelets, reperfusion, ischemia

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