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      Plasma neutrophil extracellular trap level is modified by disease severity and inhaled corticosteroids in chronic inflammatory lung diseases

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          Abstract

          A flow cytometry-based method was developed to quantify in vivo circulating neutrophil extracellular trap (NET) levels in plasma and compare them in patients with different chronic inflammatory lung diseases. Seventeen asthmatic and 11 control children, 12 adult controls, 46 asthmatic, 6 COPD and 6 adult patients with asthma-COPD overlap syndrome (ACOS) were recruited in the study. The presence of NETs in unstimulated cell-free plasma was confirmed and visualized by confocal laser-scanning microscopy. No significant differences were found in plasma NET levels between children and adults, children with or without asthma and adults with or without asthma, COPD or ACOS. When asthmatic patients were stratified according to their disease severity the average plasma NET level was significantly higher in asthmatic patients with more serious symptoms (adjusted p = 0.027). Patients with poorer pulmonary functions had higher plasma NET levels which negatively correlated with the FEV1 values (r = −0.39, p = 0.002). Patients who were medicated daily with inhaled corticosteroids (ICS) had significantly lower average plasma NET level than patients who did not or just occasionally used ICS (p = 0.027). If further studies confirm the NET-lowering effect of ICS in the circulation, it can be utilized in diseases where NETosis contributes to the pathogenesis.

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          NET balancing: a problem in inflammatory lung diseases

          Neutrophil extracellular traps (NETs) are beneficial antimicrobial defense structures that can help fight against invading pathogens in the host. However, recent studies reveal that NETs exert adverse effects in a number of diseases including those of the lung. Many inflammatory lung diseases are characterized with a massive influx of neutrophils into the airways. Neutrophils contribute to the pathology of these diseases. To date, NETs have been identified in the lungs of cystic fibrosis (CF), acute lung injury (ALI), allergic asthma, and lungs infected with bacteria, virus, or fungi. These microbes and several host factors can stimulate NET formation, or NETosis. Different forms of NETosis have been identified and are dependent on varying types of stimuli. All of these pathways however appear to result in the formation of NETs that contain DNA, modified extracellular histones, proteases, and cytotoxic enzymes. Some of the NET components are immunogenic and damaging to host tissue. Innate immune collectins, such as pulmonary surfactant protein D (SP-D), bind NETs, and enhance the clearance of dying cells and DNA by alveolar macrophages. In many inflammatory lung diseases, bronchoalveolar SP-D levels are altered and its deficiency results in the accumulation of DNA in the lungs. Some of the other therapeutic molecules under consideration for treating NET-related diseases include DNases, antiproteases, myeloperoxidase (MPO) inhibitors, peptidylarginine deiminase-4 inhibitors, and anti-histone antibodies. NETs could provide important biological advantage for the host to fight against certain microbial infections. However, too much of a good thing can be a bad thing. Maintaining the right balance of NET formation and reducing the amount of NETs that accumulate in tissues are essential for harnessing the power of NETs with minimal damage to the hosts.
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            Systemic side effects of inhaled corticosteroids in patients with asthma.

            Asthma is a complex disease of the respiratory tract associated with chronic inflammation in which an intricate network of cells and cellular factors plays a major role. Asthma is one of the most common chronic diseases, with an estimated 300 million cases worldwide, imposing a considerable burden on society in morbidity, quality of life, and healthcare costs. Inhaled corticosteroids (ICSs) form the gold standard, first-line therapy in the effective management of persistent asthma and reduce morbidity and mortality from asthma. However, long-term use of high-dose ICS therapy has potential to cause systemic side effects-impaired growth in children, decreased bone mineral density, skin thinning and bruising, and cataracts. Hypothalamic-pituitary-adrenal-axis suppression, measured by serum or urine cortisol decrease, correlates with the occurrence of systemic side effects of high-dose ICSs. Therefore, cortisol may be a relevant surrogate marker to identify the potential for adverse effects from ICS therapy. Ciclesonide is a new generation ICS with demonstrable safety and efficacy in the treatment of asthma. The unique pharmacologic characteristics of ciclesonide, such as reduced local adverse effects, lack of cortisol suppression, and the option for once-daily dosing, may improve compliance with therapy and allow long-term use of ICSs without fear of systemic adverse effects.
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              Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs.

              The formation of neutrophil extracellular traps (NETs) is a newly described phenomenon that increases the bacteria-killing ability and the inflammatory response of neutrophils. Because NET generation occurs in an inflammatory microenvironment, we examined its regulation by anti-inflammatory drugs. Treatment of neutrophils with dexamethasone had no effect, but acetylsalicylic acid (ASA) treatment prevented NET formation. NETosis was also abrogated by the presence of BAY 11-7082 [(E)-3-[4-methylphenylsulfonyl]-2-propenenitrile] and Ro 106-9920 [6-(phenylsulfinyl)tetrazolo[1,5-b]pyridazine], two structurally unrelated nuclear factor-κB (NF-κB) inhibitors. The decrease in NET formation mediated by ASA, BAY-11-7082, and Ro 106-9920 was correlated with a significant reduction in the phosphorylation of NF-κB p65 subunit, indicating that the activation of this transcription factor is a relevant signaling pathway involved in the generation of DNA traps. The inhibitory effect of these drugs was also observed when NET generation was induced under acidic or hyperthermic conditions, two stress signals of the inflammatory microenvironment. In a mouse peritonitis model, while pretreatment of animals with ASA or BAY 11-7082 resulted in a marked suppression of NET formation along with increased bacteremia, dexamethasone had no effect. Our results show that NETs have an important role in the local control of infection and that ASA and NF-κB blockade could be useful therapies to avoid undesired effect of persistent neutrophil activation.
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                Author and article information

                Contributors
                szalai.csaba@med.semmelweis-univ.hu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                9 March 2020
                9 March 2020
                2020
                : 10
                : 4320
                Affiliations
                [1 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, Department of Genetics, Cell- and Immunobiology, , Semmelweis University, ; Budapest, 1089 Hungary
                [2 ]ISNI 0000 0004 0573 5145, GRID grid.413987.0, Heim Pál Children’s Hospital, ; Budapest, 1089 Hungary
                [3 ]ISNI 0000 0004 0442 8063, GRID grid.419688.a, National Korányi Institute of TB and Pulmonology, ; Budapest, 1121 Hungary
                [4 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, Department of Pulmonology, , Semmelweis University, ; Budapest, 1083 Hungary
                [5 ]Pulmonology Hospital Törökbálint, Törökbálint, 2045 Hungary
                Article
                61253
                10.1038/s41598-020-61253-2
                7062787
                32152402
                73a28ab7-ad7e-4702-8c33-41baca210172
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 10 October 2019
                : 17 February 2020
                Funding
                Funded by: VEKOP
                Award ID: 2.3.315201600016
                Award Recipient :
                Funded by: OTKA (Hungarian Scientific Research Fund)
                Award ID: K81941
                Award Recipient :
                Funded by: NKTH (National Research and Technology)
                Award ID: TECH_08-A1/2-2008-0120
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                immunological disorders,respiratory tract diseases,cell biology,immunology,biomarkers,diseases

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