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      Extracellular histones are clinically relevant mediators in the pathogenesis of acute respiratory distress syndrome

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          Extracellular histones were recently identified as an inflammatory mediator involved in the pathogenesis of various organ injuries. This study aimed to examine extracellular histone levels and their clinical implications in acute respiratory distress syndrome (ARDS) patients and to explore histone-mediated effects through ex-vivo investigations.


          Extracellular histones, cytokine profiles and clinical data from 96 ARDS patients and 30 healthy volunteers were obtained. Human bronchial epithelial cells (BEAS-2B), human pulmonary artery endothelial cells (HPAEC), and human monocytic U937 cells were exposed to bronchoalveolar lavage fluid (BALF) collected from ARDS patients, and cellular damage and cytokine production were assessed. Furthermore, the effect of histone-targeted interventions by heparin or anti-histone antibody was evaluated.


          Plasma and BALF extracellular histone levels were much higher in ARDS patients than in healthy controls. There was a significant association between extracellular histones and ARDS severity and mortality. In addition, extracellular histones correlated with an evident systemic inflammation detected in ARDS patients. Ex-vivo analysis further showed that ARDS patient’s BALF remarkably induced epithelial and endothelial cell damage and stimulated cytokine production in the supernatant of U937 cells. The adverse effects on these cells could be abrogated by heparin or anti-histone antibody.


          Extracellular histones in ARDS patients are excessively increased and may contribute to disease aggravation by inducing cellular damage and promoting systemic inflammation. Targeting extracellular histones may provide a promising approach for treating ARDS.

          Electronic supplementary material

          The online version of this article (10.1186/s12931-017-0651-5) contains supplementary material, which is available to authorized users.

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          Most cited references 17

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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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            Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4.

            The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process.
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              Extracellular histones in tissue injury and inflammation.

              Neutrophil NETosis is an important element of host defense as it catapults chromatin out of the cell to trap bacteria, which then are killed, e.g., by the chromatin's histone component. Also, during sterile inflammation TNF-alpha and other mediators trigger NETosis, which elicits cytotoxic effects on host cells. The same mechanism should apply to other forms of regulated necrosis including pyroptosis, necroptosis, ferroptosis, and cyclophilin D-mediated regulated necrosis. Beyond these toxic effects, extracellular histones also trigger thrombus formation and innate immunity by activating Toll-like receptors and the NLRP3 inflammasome. Thereby, extracellular histones contribute to the microvascular complications of sepsis, major trauma, small vessel vasculitis as well as acute liver, kidney, brain, and lung injury. Finally, histones prevent the degradation of extracellular DNA, which promotes autoimmunization, anti-nuclear antibody formation, and autoimmunity in susceptible individuals. Here, we review the current evidence on the pathogenic role of extracellular histones in disease and discuss how to target extracellular histones to improve disease outcomes.

                Author and article information

                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                2 September 2017
                2 September 2017
                : 18
                [1 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Anesthesiology, Shanghai Pulmonary Hospital, , Tongji University School of Medicine, ; Shanghai, 200433 People’s Republic of China
                [2 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Medical Research Center, Beijing Chao-Yang Hospital, , Capital Medical University, ; Beijing, 100020 People’s Republic of China
                [3 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Thoracic Surgery, Shanghai Pulmonary Hospital, , Tongji University School of Medicine, ; Shanghai, 200433 People’s Republic of China
                [4 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Emergency, Shanghai Pulmonary Hospital, , Tongji University School of Medicine, ; Shanghai, 200433 People’s Republic of China
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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