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      ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly

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          Abstract

          In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.

          Abstract

          Highlights of basic and translational science presented at #ERSCongress 2019 summarising latest research on the lung cell atlas, lung infections, early origins of lung disease and the importance of metabolic alterations in the lung http://bit.ly/2UbdBs4

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          Most cited references51

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          Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

          Background Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. Methods A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. Findings Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50). Interpretation Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).
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            A cellular census of human lungs identifies novel cell states in health and in asthma

            Human lungs enable efficient gas exchange and form an interface with the environment, which depends on mucosal immunity for protection against infectious agents. Tightly controlled interactions between structural and immune cells are required to maintain lung homeostasis. Here, we use single-cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in healthy lungs, and lower airways in asthmatic lungs. We report location-dependent airway epithelial cell states and a novel subset of tissue-resident memory T cells. In the lower airways of patients with asthma, mucous cell hyperplasia is shown to stem from a novel mucous ciliated cell state, as well as goblet cell hyperplasia. We report the presence of pathogenic effector type 2 helper T cells (TH2) in asthmatic lungs and find evidence for type 2 cytokines in maintaining the altered epithelial cell states. Unbiased analysis of cell-cell interactions identifies a shift from airway structural cell communication in healthy lungs to a TH2-dominated interactome in asthmatic lungs.
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              Mitochondrial transfer between cells can rescue aerobic respiration.

              Current theory indicates that mitochondria were obtained 1.5 billion years ago from an ancient prokaryote. The mitochondria provided the capacity for aerobic respiration, the creation of the eukaryotic cell, and eventually complex multicellular organisms. Recent reports have found that mitochondria play essential roles in aging and determining lifespan. A variety of heritable and acquired diseases are linked to mitochondrial dysfunction. We report here that mitochondria are more dynamic than previously considered: mitochondria or mtDNA can move between cells. The active transfer from adult stem cells and somatic cells can rescue aerobic respiration in mammalian cells with nonfunctional mitochondria.
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                Author and article information

                Journal
                ERJ Open Res
                ERJ Open Res
                ERJOR
                erjor
                ERJ Open Research
                European Respiratory Society
                2312-0541
                January 2020
                02 March 2020
                : 6
                : 1
                : 00350-2019
                Affiliations
                [1 ]Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, CHUV, Lausanne, Switzerland
                [2 ]Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK
                [3 ]Dept of Pharmacology and Toxicology, Maastricht University, Maastricht, the Netherlands
                [4 ]Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the German Center of Lung Research (DZL), Munich, Germany
                [5 ]Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, Member of the DZL and the Airway Research Center North (ARCN), Borstel, Germany
                [6 ]St Vincent's University Hospital, Dublin, Ireland
                [7 ]University College Dublin School of Medicine, Dublin, Ireland
                [8 ]University of Technology Sydney, Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, Sydney, Australia
                [9 ]University of Groningen, University Medical Center Groningen, Depts of Pathology & Medical Biology and Pulmonology, Groningen, The Netherlands
                [10 ]Dept of Pulmonology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
                [11 ]Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the DZL, Munich, Germany
                [12 ]University of Vermont, Dept of Medicine, Larner College of Medicine, Burlington, VT, USA
                [13 ]Lund University, Dept of Experimental Medical Science, Lund, Sweden
                Author notes
                Sabine Bartel, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. E-mail: s.r.bartel@ 123456umcg.nl
                Author information
                https://orcid.org/0000-0002-0682-4022
                https://orcid.org/0000-0002-0238-5982
                https://orcid.org/0000-0002-9163-795X
                Article
                00350-2019
                10.1183/23120541.00350-2019
                7049707
                de2c9fb7-223f-40bd-84b6-9eaa9155786f
                Copyright ©ERS 2020

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                History
                : 16 December 2019
                : 26 January 2020
                Categories
                Congress Highlights
                12

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