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      Porphyromonas gingivalis Participates in Pathogenesis of Human Abdominal Aortic Aneurysm by Neutrophil Activation. Proof of Concept in Rats

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          Abstract

          Background

          Abdominal Aortic Aneurysms (AAAs) represent a particular form of atherothrombosis where neutrophil proteolytic activity plays a major role. We postulated that neutrophil recruitment and activation participating in AAA growth may originate in part from repeated episodes of periodontal bacteremia.

          Methods and Findings

          Our results show that neutrophil activation in human AAA was associated with Neutrophil Extracellular Trap (NET) formation in the IntraLuminal Thrombus, leading to the release of cell-free DNA. Human AAA samples were shown to contain bacterial DNA with high frequency (11/16), and in particular that of Porphyromonas gingivalis ( Pg), the most prevalent pathogen involved in chronic periodontitis, a common form of periodontal disease. Both DNA reflecting the presence of NETs and antibodies to Pg were found to be increased in plasma of patients with AAA. Using a rat model of AAA, we demonstrated that repeated injection of Pg fostered aneurysm development, associated with pathological characteristics similar to those observed in humans, such as the persistence of a neutrophil-rich luminal thrombus, not observed in saline-injected rats in which a healing process was observed.

          Conclusions

          Thus, the control of periodontal disease may represent a therapeutic target to limit human AAA progression.

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          Most cited references54

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          Netting neutrophils in autoimmune small-vessel vasculitis.

          Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
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            Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

            Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.
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              Abdominal aortic aneurysm.

              Abdominal aortic aneurysms cause 1.3% of all deaths among men aged 65-85 years in developed countries. These aneurysms are typically asymptomatic until the catastrophic event of rupture. Repair of large or symptomatic aneurysms by open surgery or endovascular repair is recommended, whereas repair of small abdominal aortic aneurysms does not provide a significant benefit. Abdominal aortic aneurysm is linked to the degradation of the elastic media of the atheromatous aorta. An inflammatory cell infiltrate, neovascularisation, and production and activation of various proteases and cytokines contribute to the development of this disorder, although the underlying mechanisms are unknown. In this Seminar, we aim to provide an updated review of the pathophysiology, current and new diagnostic procedures, assessment, and treatment of abdominal aortic aneurysm to provide family practitioners with a working knowledge of this disorder.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                13 April 2011
                : 6
                : 4
                : e18679
                Affiliations
                [1 ]INSERM (Institut National de la Santé et de la Recherche Médicale) U698, Paris, France
                [2 ]Université Denis Diderot, Paris, France
                [3 ]Service de chirurgie thoracique et vasculaire, Hôpital Xavier Bichat-Claude Bernard, APHP (Assistance Publique Hôpitaux de Paris), Paris, France
                [4 ]Service de chirurgie cardiovasculaire, Hôpital Européen Georges Pompidou, APHP (Assistance Publique Hôpitaux de Paris), Paris, France
                [5 ]Equipe de Microbiologie, UPRES-EA (Unité Propre de Recherche de l'Enseignement Superieur-Equipe d'Accueil) 1254, Université Européenne de Bretagne, Université de Rennes I, Rennes, France
                [6 ]Service de bactériologie et virologie, Hôpital Xavier Bichat-Claude Bernard, APHP (Assistance Publique Hôpitaux de Paris), Paris, France
                [7 ]CHU (Centre Hospitalier Universitaire) de Nancy, CIC (Centre d'Investigation Clinique); CIC9501; Université Nancy, Faculté de Médecine; Inserm, U961, Vandoeuvre lès Nancy, France; Service de médecine vasculaire et hypertension, Hôpital Européen Georges Pompidou, Paris, France
                [8 ]Département de Parodontologie, Service d'odontologie, Hôpital Garancière Rothschild, APHP (Assistance Publique Hôpitaux de Paris), Paris, France
                Leiden University Medical Center, Netherlands
                Author notes

                Conceived and designed the experiments: OM SD J-BM. Performed the experiments: SD J-MA CJ LL OM. Analyzed the data: SD CJ OM PR. Contributed reagents/materials/analysis tools: MB-M PR LL YC RR. Wrote the paper: OM SD J-BM PB.

                Article
                PONE-D-10-06667
                10.1371/journal.pone.0018679
                3076426
                21533243
                c72f3987-3e5f-47dc-af0c-aade440776c7
                Delbosc 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
                : 15 December 2010
                : 8 March 2011
                Page count
                Pages: 17
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Cardiovascular System
                Model Organisms
                Animal Models
                Rat
                Medicine
                Cardiovascular
                Aortic Diseases
                Vascular Biology
                Clinical Research Design
                Animal Models of Disease
                Infectious Diseases
                Bacterial Diseases
                Periodontal Abscesses
                Oral Medicine
                Dentistry

                Uncategorized
                Uncategorized

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