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      Caspase-1-Dependent Pyroptosis of Peripheral Blood Mononuclear Cells Is Associated with the Severity and Mortality of Septic Patients

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          Abstract

          Purpose

          Pyroptosis has been known to play a vital role in the inflammation process which was induced by infection, injury, or inflammatory disease. The present study was aimed at evaluating the percentage of peripheral blood mononuclear cell (PBMC) pyroptosis in septic patients and assessing the correlation of PBMC pyroptosis with the severity and the mortality of septic patients.

          Methods

          128 trauma-induced patients with sepsis were enrolled in this prospective cohort study. Blood samples were collected, and PBMC pyroptosis was measured by flow cytometry within 24 hours after sepsis was diagnosed.

          Results

          Percentage of PBMC pyroptosis was positively correlated with the acute physiology and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score (all P < 0.01). The area under the curve (AUC) for the percentage of PBMC pyroptosis on a receiver operating characteristic curve was 0.79 (95% confidence interval (CI), 0.68–0.90). A Cox proportional hazard model identified an association between an increased percentage of PBMC pyroptosis (>14.17%) and increased risk of the 28-day mortality (hazard ratio = 1.234, 95% CI, 1.014–1.502).

          Conclusion

          The percentage of PBMC pyroptosis increases in septic patients, and the increased percentage of PBMC pyroptosis is associated with the severity of sepsis and the 28-day mortality of patients with sepsis.

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          Most cited references20

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          Pyroptosis.

          Injury and physical trauma may inflict accidental cell death, but we have come to realize during the past four decades that cells may also actively engage cell death when needed. These regulated cell death forms are intrinsically connected with human embryonic development, homeostatic maintenance and disease pathology. For instance, the human body is composed of approximately 10(14) cells, millions of which are removed daily by apoptosis and replaced with newly differentiated cells in order to secure organ functionality. Apoptotic cells are orderly packed in 'apoptotic bodies' for uptake by neighboring cells and professional phagocytes, thereby avoiding deleterious inflammatory responses by circulating leukocytes. Unlike apoptosis, however, more recently identified forms of regulated cell death - such as necroptosis and pyroptosis - are characterized by an early breach of the plasma membrane integrity, which results in extracellular spilling of the intracellular contents. Here, we will describe and discuss this and other features of pyroptosis.
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            Interleukin-18 regulates both Th1 and Th2 responses.

            Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-gamma. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglia. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.
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              IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation.

              IL-1 beta-converting enzyme (ICE; caspase-1) is the intracellular protease that cleaves the precursors of IL-1 beta and IL-18 into active cytokines. In the present study, the effect of ICE deficiency was evaluated during experimental colitis in mice. In acute dextran sulfate sodium-induced colitis, ICE-deficient (ICE KO) mice exhibited a greater than 50% decrease of the clinical scores weight loss, diarrhea, rectal bleeding, and colon length, whereas daily treatment with IL-1 receptor antagonist revealed a modest reduction in colitis severity. To further characterize the function of ICE and its role in intestinal inflammation, chronic colitis was induced over a 30-day time period. During this chronic time course, ICE KO mice exhibited a near complete protection, as reflected by significantly reduced clinical scores and almost absent histological signs of colitis. Consistently, colon shortening occurred only in dextran sulfate sodium-exposed wild-type mice but not in ICE KO mice. Protection was accompanied by reduced spontaneous release of the proinflammatory cytokines IL-18, IL-1 beta, and IFN-gamma from total colon cultures. In addition, flow cytometric analysis of isolated mesenteric lymph node cells revealed evidence of reduced cell activation in ICE KO mice as evaluated by surface expression of CD3 CD69 and CD4 CD25. We conclude that inhibition of ICE represents a novel anti-inflammatory strategy for intestinal inflammation.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2020
                28 February 2020
                : 2020
                : 9152140
                Affiliations
                1Trauma Center/Department of Emergency and Trauma Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China
                2Plastic and Aesthetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
                Author notes

                Academic Editor: Rudolf K. Braun

                Author information
                https://orcid.org/0000-0002-7916-0992
                Article
                10.1155/2020/9152140
                7066402
                32258157
                22b8406c-978b-406b-8c4f-f4f7b4b367d9
                Copyright © 2020 Yuchang Wang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 August 2019
                : 17 January 2020
                Funding
                Funded by: Natural Science Foundation of Hubei Province
                Award ID: 2013CFA075
                Funded by: 12th Five-Year Plan of China
                Award ID: 2012BAI11B00
                Funded by: Technology Research Plan of Wuhan
                Award ID: 2015060101010035
                Funded by: National Natural Science Foundation of China
                Award ID: 81772129
                Award ID: 81571891
                Categories
                Research Article

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