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      Gender differences in sepsis : Cardiovascular and immunological aspects

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          Abstract

          During sepsis, a complex network of cytokine, immune, and endothelial cell interactions occur and disturbances in the microcirculation cause organ dysfunction or even failure leading to high mortality in those patients. In this respect, numerous experimental and clinical studies indicate sex-specific differences in infectious diseases and sepsis.

          Female gender has been demonstrated to be protective under such conditions, whereas male gender may be deleterious due to a diminished cell-mediated immune response and cardiovascular functions. Male sex hormones, i.e., androgens, have been shown to be suppressive on cell-mediated immune responses. In contrast, female sex hormones exhibit protective effects which may contribute to the natural advantages of females under septic conditions. Thus, the hormonal status has to be considered when treating septic patients.

          Therefore, potential therapies could be derived from this knowledge. In this respect, administration of female sex hormones (estrogens and their precursors) may exert beneficial effects. Alternatively, blockade of male sex hormone receptors could result in maintained immune responses under adverse circulatory conditions. Finally, administration of agents that influence enzymes synthesizing female sex hormones which attenuate the levels of pro-inflammatory agents might exert salutary effects in septic patients. Prospective patient studies are required for transferring those important experimental findings into the clinical arena.

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          Most cited references68

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          Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock.

          IL-1 beta-converting enzyme (ICE) cleaves pro-IL-1 beta to generate mature IL-1 beta. ICE is homologous to other proteins that have been implicated in apoptosis, including CED-3 and Nedd-2/lch-1. We generated ICE-deficient mice and observed that they are overtly normal but have a major defect in the production of mature IL-1 beta after stimulation with lipopolysaccharide. IL-1 alpha production is also impaired. ICE-deficient mice are resistant to endotoxic shock. Thymocytes and macrophages from the ICE-deficient animals undergo apoptosis normally. ICE therefore plays a dominant role in the generation of mature IL-1 beta, a previously unsuspected role in production of IL-1 alpha, but has no autonomous function in apoptosis.
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            Gender differences in human sepsis.

            In animal studies, gender differences were related to hormonal and immunologic changes that were associated with an increased susceptibility to sepsis in males. In a prospective study, gender differences in patients with surgical sepsis were evaluated in terms of survival, sex hormones, and proinflammatory as well as anti-inflammatory mediators. Surgical intensive care unit of a university hospital. Fifty-two patients (19 women and 33 men) with surgical sepsis. In a prospective study, tumor necrosis factor alpha and interleukin 6 bioactivity and plasma levels of interleukin 10 (using enzyme-linked immunosorbent assay), total testosterone, and 17-beta estradiol (using radioimmunoassay) were determined on days 1, 3, 5, 7, 10, and 14 after diagnosis of sepsis. There were no differences in characteristics of patients in age (mean age, 55.4 years for women and 53.1 years for men) or cause and severity of sepsis (Acute Physiology and Chronic Health Evaluation II score, 17.3 for women and 18.5 for men; multiple organ dysfunction score, 9.9 vs 10.8, respectively). Although no difference could be found in the multiple organ dysfunction score from day 1 to day 28, the prognosis of sepsis was significantly different in women compared with men. Hospital-mortality rate was 70% (23 of 33 patients) in male and 26% (5 of 19) in female patients (P<.008, log-rank test). Bioactivity of tumor necrosis factor continuously increased in men after diagnosis of sepsis, with significantly elevated levels on day 10 (P<.05, Mann-Whitney U test with Bonferroni correction), whereas no difference was found for interleukin 6 bioactivity. Women displayed enhanced interleukin 10 levels compared with men from day 1 to day 10 that reached a significant difference on days 3 and 5 (P<.05). Total testosterone levels were below the normal range for men, and estradiol levels were initially increased in both men and postmenopausal women, with higher levels for women. In this prospective study, gender differences were confirmed in human sepsis, with a significantly better prognosis for women, which may be related to increased levels of anti-inflammatory mediators. The hypothetical different ratio of proinflammatory and anti-inflammatory mediators may be important for further therapeutic interventions in sepsis.
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              Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity.

              Though gender-based differences in the development of protective or pathological adaptive host responses have been widely noted, it is becoming apparent that sex may also influence the early perception of microbial challenges and the generation of inflammatory immune responses. These differences may be due to the actions of reproductive hormones, and such a hypothesis is supported by the presence of receptors for these hormones in a variety of immune cell types. Androgens such as testosterone have been shown to decrease immune functions, including cytokine production. However, the mechanisms by which testosterone limits such responses remain undefined. In this study, we have investigated the acute effects of testosterone on the level of expression of a key trigger for inflammation and innate immunity, Toll-like receptor 4 (TLR4), on isolated mouse macrophages. We show that in vitro testosterone treatment of macrophages, generated in the absence of androgen, elicits a modest but significant decrease in TLR4 expression and sensitivity to a TLR4-specific ligand. In addition, we have studied the effect of in vivo removal of endogenous testosterone on TLR4 expression and endotoxin susceptibility. We report that orchidectomized mice were significantly more susceptible to endotoxic shock and show that macrophages isolated from these animals have significantly higher TLR4 cell surface expression than those derived from sham gonadectomized mice. Importantly, these effects were not apparent in orchidectomized animals that received exogenous testosterone treatment. As such, these data may represent an important mechanism underlying the immunosuppressive effects of testosterone.
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                Author and article information

                Journal
                Virulence
                Virulence
                VIRU
                Virulence
                Landes Bioscience
                2150-5594
                2150-5608
                01 January 2014
                05 November 2013
                05 November 2013
                : 5
                : 1
                : 12-19
                Affiliations
                [1 ]Department of Surgery; Klinikum Grosshadern; Munich, Germany
                [2 ]Center for Surgical Research; University of Alabama at Birmingham; Birmingham, AL USA
                Author notes
                [* ]Correspondence to: Irshad H Chaudry, Email: IChaudry@ 123456uabmc.edu
                Article
                2013VIRULENCE0072R 26982
                10.4161/viru.26982
                3916365
                24193307
                dece026b-17e8-4d6d-95f7-8e04228a845b
                Copyright © 2014 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 30 July 2013
                : 25 October 2013
                : 28 October 2013
                Categories
                Review

                Infectious disease & Microbiology
                sex steroids,estrogen,immune depression,immune modulation
                Infectious disease & Microbiology
                sex steroids, estrogen, immune depression, immune modulation

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