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      Skin Biopsies Demonstrate Site-Specific Endothelial Activation in Mouse Models of Sepsis

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          Abstract

          Background/Aims: Skin biopsies allow for direct phenotyping of the endothelium in clinical settings. Objectives: We hypothesize that in murine sepsis endothelial activation is manifested by changes in protein and mRNA expression in skin biopsies, and that such alterations differ from other organs. Methods: In two mouse models of sepsis [endotoxemia and cecal ligation puncture (CLP)], we measured circulating levels of endothelial biomarkers, quantitated mRNA expression of activation markers and assayed for protein expression using immunohistochemistry. Results: Endotoxemic mice demonstrated increased circulating levels of sE-selectin, sICAM-1, sVCAM-1 and sP-selectin at 24 h, while CLP was associated with increased levels of sE-selectin alone. In real-time PCR, mRNA levels for P-selectin, ICAM-1 and PAI-1 were increased in skin from endotoxemic mice. In CLP, mRNA levels for P-selectin, ICAM-1, E-selectin and PAI-1 were elevated, while VCAM-1 expression was reduced in skin. Most, but not all of these changes correlated with alterations in immunohistochemical staining. Expression patterns in skin differed from those in brain, heart, and lung. Conclusions: Skin biopsies demonstrated endothelial cell activation during sepsis. The expression patterns differed by type of sepsis model and between vascular beds of skin, brain, heart, and lung, providing a foundation for identifying skin microvascular-bed-specific molecule signatures.

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          Most cited references 15

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          The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study.

          Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. Prospective cohort study with a follow-up of 28 days or until discharge if earlier. Three intensive care units and three general wards in a tertiary health care institution. Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count. Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death. During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857, 804, and 542 episodes per 1000 patient-days, respectively, and 671, 495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations. This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock.
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            Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.

            Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the second of a 2-part review on the phenotypic heterogeneity of blood vessel endothelial cells. The first part discusses the scope, the underlying mechanisms, and the diagnostic and therapeutic implications of phenotypic heterogeneity. Here, these principles are applied to an understanding of organ-specific phenotypes in representative vascular beds including arteries and veins, heart, lung, liver, and kidney. The goal is to underscore the importance of site-specific properties of the endothelium in mediating homeostasis and focal vascular pathology, while at the same time emphasizing the value of approaching the endothelium as an integrated system.
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              Has the mortality of septic shock changed with time.

              To determine whether a systematic review of the literature could identify changes in the mortality of septic shock over time. A review of all relevant papers from 1958 to August 1997, identified through a MEDLINE search and from the bibliographies of articles identified. The search identified 131 studies (99 prospective and 32 retrospective) involving a total of 10,694 patients. The patients' mean age was 57 yrs with no change over time. The overall mortality rate in the 131 studies was 49.7%. There was an overall significant trend of decreased mortality over the period studied (r=.49, p < .05). The mortality rate in those patients with bacteremia as an entry criterion was greater than that rate in patients whose entry criterion was sepsis without definite bacteremia (52.1% vs. 49.1%; chi2=6.1 and p< .05). The site of infection altered noticeably over the years. Chest-related infections increased over time, with Gram-negative infections becoming proportionately less common. If all other organisms and mixed infections are included with the Gram-positives, the result is more dramatic, with these organisms being causative in just 10% of infections between 1958 and 1979 but in 31% of infections between 1980 and 1997. The present review showed a slight reduction in mortality from septic shock over the years, although this result should be approached with caution. The heterogeneity of the articles and absence of a severity score for most of the studies limited our analysis. Furthermore, there was an increasing prevalence of Gram-positive causative organisms, and a change of the predominant origin of sepsis from the abdomen to the chest.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2009
                August 2009
                04 April 2009
                : 46
                : 5
                : 495-502
                Affiliations
                aDepartment of Emergency Medicine and bCenter for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, Mass., USA
                Article
                210662 J Vasc Res 2009;46:495–502
                10.1159/000210662
                19346756
                © 2009 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 29, Pages: 8
                Categories
                Research Paper

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