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      Increased extracellular vesicle miRNA-466 family in the bronchoalveolar lavage fluid as a precipitating factor of ARDS

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          Abstract

          Background

          Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS.

          Methods

          Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model.

          Results

          Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1β) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1β expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs.

          Conclusions

          These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.

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          Most cited references11

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          Molecular mechanisms regulating NLRP3 inflammasome activation.

          Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inflammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome.
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            MicroRNAs: synthesis, mechanism, function, and recent clinical trials.

            MicroRNAs (miRNAs) are a class of small, endogenous RNAs of 21-25 nucleotides (nts) in length. They play an important regulatory role in animals and plants by targeting specific mRNAs for degradation or translation repression. Recent scientific advances have revealed the synthesis pathways and the regulatory mechanisms of miRNAs in animals and plants. miRNA-based regulation is implicated in disease etiology and has been studied for treatment. Furthermore, several preclinical and clinical trials have been initiated for miRNA-based therapeutics. In this review, the existing knowledge about miRNAs synthesis, mechanisms for regulation of the genome, and their widespread functions in animals and plants is summarized. The current status of preclinical and clinical trials regarding miRNA therapeutics is also reviewed. The recent findings in miRNA studies, summarized in this review, may add new dimensions to small RNA biology and miRNA therapeutics. Copyright © 2010 Elsevier B.V. All rights reserved.
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              Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.

              Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12h after LPS treatment or CLP surgery, WT mice pre-treated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.
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                Author and article information

                Contributors
                shikano.sotaro@nihon-u.ac.jp
                gon.yasuhiro@nihon-u.ac.jp
                maruoka.shuichiro@nihon-u.ac.jp
                shimizu.tetsuo@nihon-u.ac.jp
                kozu.yutaka@nihon-u.ac.jp
                iida.yuko@nihon-u.ac.jp
                mema15012@g.nihon-u.ac.jp
                mema15010@g.nihon-u.ac.jp
                mesi15009@g.nihon-u.ac.jp
                meko15011@g.nihon-u.ac.jp
                corochami@gmail.com
                +81-3-3972-8111 , mizumura.kenji@nihon-u.ac.jp
                hashimoto.shu@nihon-u.ac.jp
                Journal
                BMC Pulm Med
                BMC Pulm Med
                BMC Pulmonary Medicine
                BioMed Central (London )
                1471-2466
                20 June 2019
                20 June 2019
                2019
                : 19
                : 110
                Affiliations
                ISNI 0000 0001 2149 8846, GRID grid.260969.2, Division of Respiratory Medicine, Department of Internal Medicine, , Nihon University School of Medicine, ; Tokyo, Japan
                Author information
                http://orcid.org/0000-0001-8532-9670
                Article
                876
                10.1186/s12890-019-0876-9
                6584994
                31221118
                4cdf32a2-5817-4e1f-86d0-f5a9bd1bdae2
                © The Author(s). 2019

                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.

                History
                : 31 October 2018
                : 11 June 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 15K09196
                Award Recipient :
                Funded by: Strategic Research Foundation for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan
                Award ID: S1511014
                Award Recipient :
                Funded by: Nihon University President’s Grant for Multidisciplinary Research
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Respiratory medicine
                ards,extracellular vesicles,mirna,nlrp3 inflammasome
                Respiratory medicine
                ards, extracellular vesicles, mirna, nlrp3 inflammasome

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