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      Senescence and autophagy in usual interstitial pneumonia of different etiology

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          Abstract

          Idiopathic pulmonary fibrosis (IPF) is a disease with a dismal prognosis. Currently, the causing agent(s) are poorly understood. Recent data suggest that senescence and autophagy might play a role in its development, as well as changes in metabolism due to hypoxic conditions. In this study, the expression of senescence markers in 23 cases of usual interstitial pneumonia (UIP)/IPF and UIP/chronic autoimmune diseases (UIP/AuD) was investigated. The status of autophagy was evaluated with respect to either antiinflammatory or antihypoxia function. Formalin-fixed paraffin-embedded tissues of UIP were selected for immunohistochemistry with antibodies for p21, p16, and β-galactosidase (senescence); for LC3, SIRT1, MAP1S, and pAMKα (autophagy); and for LDH and GLUT1 (metabolism). Epithelial cells in cystic remodeled areas of UIP stained for p16 and p21, p16 being more specific compared with p21. Myofibroblasts were negative in all cases. An upregulation of all four autophagy markers was seen not only in epithelia within remodeled areas and proliferating myofibroblasts, but also in bronchial epithelia and pneumocytes. Upregulated autophagy points to a compensatory mechanism for hypoxia; therefore, LDH and GLUT1 were investigated. Their expression was present in epithelia within cystic remodeling and in myofibroblasts. The cells within the remodeled areas stained for cytokeratin 5, but coexpressed TTF1, confirming their origin from basal cells of bronchioles. Within this population, senescent cells arise. Our results indicated that autophagy in UIP very likely helps cells to survive in hypoxic condition. By phagocytosis of cellular debris, they supplement their need for nutrition, and by upregulating LDH and GLUT1, they compensate for local hypoxia.

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          Hallmarks of Cellular Senescence

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            The role of senescent cells in ageing.

            Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan.
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              Cellular senescence mediates fibrotic pulmonary disease

              Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.
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                Author and article information

                Contributors
                helmut.popper@medunigraz.at
                Journal
                Virchows Arch
                Virchows Arch
                Virchows Archiv
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0945-6317
                1432-2307
                27 August 2020
                27 August 2020
                2021
                : 478
                : 3
                : 497-506
                Affiliations
                [1 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Diagnostic and Research Institute of Pathology, , Medical University of Graz, ; Neue Stiftingtalstrasse 6, 8010 Graz, Austria
                [2 ]Pulmonology Department, Clinics Munich-Bogenhausen, Munich, Germany
                [3 ]Pathology Department, Clinics Munich-Bogenhausen, Munich, Germany
                Author information
                http://orcid.org/0000-0003-4970-1265
                Article
                2917
                10.1007/s00428-020-02917-2
                7973921
                32851507
                12ad2328-1c15-4f7e-8e27-89ad00ba2aef
                © 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 April 2020
                : 15 July 2020
                : 19 August 2020
                Funding
                Funded by: Medical University of Graz
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Pathology
                ipf,uip,senescence,p16,autophagy,lc3,sirt,map1s,pamkα,regeneration in cysts,cytokeratin 5,ttf1,myofibroblast,hypoxia,ldh,glut1
                Pathology
                ipf, uip, senescence, p16, autophagy, lc3, sirt, map1s, pamkα, regeneration in cysts, cytokeratin 5, ttf1, myofibroblast, hypoxia, ldh, glut1

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