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      The Role of Herpes Viruses in Pulmonary Fibrosis

      systematic-review

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          Abstract

          Pulmonary fibrosis (PF) is a serious lung disease which can result from known genetic or environmental exposures but is more commonly idiopathic (IPF). In familial PF (FPF), the majority of identified causal genes play key roles in the maintenance of telomeres, the protective end structures of chromosomes. Recent evidence suggests that short telomeres may also be implicated causally in a significant proportion of idiopathic cases. The possible involvement of herpes viruses in PF disease incidence and progression has been examined for many years, with some studies showing strong, statistically significant associations and others reporting no involvement. Evidence is thus polarized and remains inconclusive. Here we review the reported involvement of herpes viruses in PF in both animals and humans and present a summary of the evidence to date. We also present several possible mechanisms of action of the different herpes viruses in PF pathogenesis, including potential contributions to telomere attrition and cellular senescence. Evidence for antiviral treatment in PF is very limited but suggests a potential benefit. Further work is required to definitely answer the question of whether herpes viruses impact PF disease onset and progression and to enable the possible use of targeted antiviral treatments to improve clinical outcomes.

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          Most cited references118

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          An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management

          American Journal of Respiratory and Critical Care Medicine, 183(6), 788-824
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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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              Telomerase mutations in families with idiopathic pulmonary fibrosis.

              Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis. To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR. Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families. Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease. Copyright 2007 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                22 July 2021
                2021
                : 8
                : 704222
                Affiliations
                [1] 1College of Medicine and Health, University of Exeter , Exeter, United Kingdom
                [2] 2Department of Medicine, University of Auckland , Auckland, New Zealand
                [3] 3Dyskeratosis Congenita (DC) Action , London, United Kingdom
                Author notes

                Edited by: Elena Lopez-Rodriguez, Charité-Universitätsmedizin Berlin, Germany

                Reviewed by: Raquel Arroyo, Cincinnati Children's Hospital Medical Center, United States; Stephen James Gurczynski, University of Michigan, United States

                *Correspondence: Anna Duckworth ad653@ 123456exeter.ac.uk

                This article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine

                †These authors have contributed equally to this work

                Article
                10.3389/fmed.2021.704222
                8339799
                34368196
                32292909-b263-429b-9c7a-4f758732b3e3
                Copyright © 2021 Duckworth, Longhurst, Paxton and Scotton.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 May 2021
                : 24 June 2021
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 122, Pages: 15, Words: 12494
                Categories
                Medicine
                Systematic Review

                pulmonary fibrosis,herpes virus,cmv,ebv,telomeres,senescence,endoplasmic reticulum stress,antiviral treatment

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