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      Shared Features of Endothelial Dysfunction between Sepsis and Its Preceding Risk Factors (Aging and Chronic Disease)

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          Abstract

          Acute vascular endothelial dysfunction is a central event in the pathogenesis of sepsis, increasing vascular permeability, promoting activation of the coagulation cascade, tissue edema and compromising perfusion of vital organs. Aging and chronic diseases (hypertension, dyslipidaemia, diabetes mellitus, chronic kidney disease, cardiovascular disease, cerebrovascular disease, chronic pulmonary disease, liver disease, or cancer) are recognized risk factors for sepsis. In this article we review the features of endothelial dysfunction shared by sepsis, aging and the chronic conditions preceding this disease. Clinical studies and review articles on endothelial dysfunction in sepsis, aging and chronic diseases available in PubMed were considered. The main features of endothelial dysfunction shared by sepsis, aging and chronic diseases were: (1) increased oxidative stress and systemic inflammation, (2) glycocalyx degradation and shedding, (3) disassembly of intercellular junctions, endothelial cell death, blood-tissue barrier disruption, (4) enhanced leukocyte adhesion and extravasation, (5) induction of a pro-coagulant and anti-fibrinolytic state. In addition, chronic diseases impair the mechanisms of endothelial reparation. In conclusion, sepsis, aging and chronic diseases induce similar features of endothelial dysfunction. The potential contribution of pre-existent endothelial dysfunction to sepsis pathogenesis deserves to be further investigated.

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          Most cited references95

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones

            Neutrophils play an important role in innate immunity by defending the host organism against invading microorganisms. Antimicrobial activity of neutrophils is mediated by release of antimicrobial peptides, phagocytosis as well as formation of neutrophil extracellular traps (NET). These structures are composed of DNA, histones and granular proteins such as neutrophil elastase and myeloperoxidase. This study focused on the influence of NET on the host cell functions, particularly on human alveolar epithelial cells as the major cells responsible for gas exchange in the lung. Upon direct interaction with epithelial and endothelial cells, NET induced cytotoxic effects in a dose-dependent manner, and digestion of DNA in NET did not change NET-mediated cytotoxicity. Pre-incubation of NET with antibodies against histones, with polysialic acid or with myeloperoxidase inhibitor but not with elastase inhibitor reduced NET-mediated cytotoxicity, suggesting that histones and myeloperoxidase are responsible for NET-mediated cytotoxicity. Although activated protein C (APC) did decrease the histone-induced cytotoxicity in a purified system, it did not change NET-induced cytotoxicity, indicating that histone-dependent cytotoxicity of NET is protected against APC degradation. Moreover, in LPS-induced acute lung injury mouse model, NET formation was documented in the lung tissue as well as in the bronchoalveolar lavage fluid. These data reveal the important role of protein components in NET, particularly histones, which may lead to host cell cytotoxicity and may be involved in lung tissue destruction.
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              Sepsis and septic shock.

              For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15-25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30-50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                30 October 2018
                November 2018
                : 7
                : 11
                : 400
                Affiliations
                [1 ]Group for Biomedical Research in Sepsis (Bio∙Sepsis), Hospital Clínico Universitario de Valladolid/IECSCYL, Av. Ramón y Cajal, 3, 47003 Valladolid, Spain; xtina.lopez.mestanza@ 123456hotmail.com (C.L.-M.); ralmansa@ 123456saludcastillayleon.es (R.A.)
                [2 ]Centro de Investigación Biomedica En Red-Enfermedades Respiratorias (CibeRes, CB06/06/0028), Instituto de salud Carlos III (ISCIII), Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
                [3 ]Anesthesiology and Reanimation Service, Hospital General Universitario Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; patriduque@ 123456gmail.com
                Author notes
                [* ]Correspondence: jfbermejo@ 123456saludcastillayleon.es (J.F.B.-M.); mmartin.iecscyl@ 123456saludcastillayleon.es (M.M.-F.); Tel.: +34-983-420-000 (ext. 87422) (J.F.B.-M.); +34-983-420-000 (ext. 87987) (M.M.-F.)
                [†]

                These authors contributed equally to this work.

                Article
                jcm-07-00400
                10.3390/jcm7110400
                6262336
                30380785
                23e60239-eb54-497c-bc20-20b36b937179
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 September 2018
                : 27 October 2018
                Categories
                Review

                aging,chronic disease,endothelium dysfunction,sepsis
                aging, chronic disease, endothelium dysfunction, sepsis

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