5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      AGER expression and alternative splicing in bronchial biopsies of smokers and never smokers

      letter

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Cigarette smoking is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Evidence is accumulating that Receptor for Advanced Glycation-End products (RAGE)-signaling is a key pathway in the pathophysiology of COPD. To date, it is unknown how smoking affects RAGE expression. In the current study, we investigated the effect of smoking on AGER, the gene encoding RAGE, expression and on alternative splicing of AGER. To this end, we conducted RNA-Seq on bronchial biopsies for asymptomatic smokers ( n = 36) and never smokers ( n = 40). Total AGER gene expression was accessed using DESeq2, while alternative splicing was investigated by measuring the number of specific split reads spanning exon-exon junctions and the total split reads. One of the major isoforms of RAGE is endogenous soluble (es) RAGE, an anti-inflammatory decoy receptor, making up for approximately 10% of the total amount of soluble (s)RAGE. We found that smokers show decreased total gene expression of AGER in bronchial biopsies, while the relative abundance of the esRAGE isoform is increased. Furthermore, no difference in the serum levels of total sRAGE were observed between smokers and non-smokers. Our data indicates that smoking initiates a protective anti-inflammatory mechanism with decreased expression of the pro-inflammatory gene AGER and increased relative abundance of the anti-inflammatory isoform esRAGE.

          Related collections

          Most cited references10

          • Record: found
          • Abstract: found
          • Article: not found

          DAMPs activating innate and adaptive immune responses in COPD.

          Chronic obstructive pulmonary disease (COPD), a progressive lung disease characterized by sustained neutrophilic airway inflammation, is caused by chronic exposure to noxious stimuli, e.g., cigarette smoke. This chronic exposure can induce immunogenic cell death of structural airway cells, inducing the release of damage-associated molecular patterns (DAMPs). Levels of several DAMPs, including S100 proteins, defensins, and high-mobility group box-1 (HMGB1), are increased in extracellular lung fluids of COPD patients. As DAMPs can attract and activate immune cells upon binding to pattern recognition receptors, we propose that their release may contribute to neutrophilic airway inflammation. In this review, we discuss the novel role of DAMPs in COPD pathogenesis. Relevant DAMPs are categorized based on their subcellular origin, i.e. cytoplasm, endoplasmic reticulum, nucleus, and mitochondria. Furthermore, their potential role in the pathophysiology of COPD will be discussed.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Role of Advanced Glycation End Products and Its Receptors in the Pathogenesis of Cigarette Smoke-Induced Cardiovascular Disease.

            The interaction of advanced glycation end products (AGEs) with its cell-bound receptor RAGE increases gene expression and release of proinflammatory cytokines and increase generation of reactive oxygen species (ROS). Circulating receptors, soluble RAGE (sRAGE), and endosecretory RAGE (esRAGE) by binding with RAGE ligands have protective effects against AGE-RAGE interaction. Cigarette smoking is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This article reviews; if the AGE-RAGE axis is involved in the cigarette smoke-induced cardiovascular diseases. There are various sources of AGEs in smokers including, gas/tar of cigarette, activation of macrophages and polymorphonuclear leukocytes, uncoupling of endothelial isoform of nitric oxide synthase (eNOS) and xanthine oxidase. The levels of AGEs are elevated in smokers. Serum levels of sRAGE have been reported to be reduced, elevated, or unchanged in smokers. Mostly the levels are reduced. There is one article which shows an elevation of levels of sRAGE in smokers. Serum levels of esRAGE are unaltered in smokers. Mechanism of AGE-RAGE-induced atherosclerosis has been discussed. Atherosclerosis leads to the cardiovascular diseases. It has been suggested that ratio of AGE/sRAGE or AGE/esRAGE is useful in determining the deleterious effects of AGE-RAGE interaction in smokers. sRAGE alone is not a good marker for smoke-induced cardiovascular disease. In conclusion cigarette smoke induces formation of AGEs and reduces sRAGE resulting in the development of atherosclerosis and related coronary heart disease, stroke, and peripheral vascular disease. Ratio of AGEs/sRAGE is a better marker for cardiovascular disease than AGEs or sRAGE alone in smokers.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              RAGE and tobacco smoke: insights into modeling chronic obstructive pulmonary disease

              Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by chronic airway inflammation and airspace remodeling, leading to airflow limitation that is not completely reversible. Smoking is the leading risk factor for compromised lung function stemming from COPD pathogenesis. First- and second-hand cigarette smoke contain thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic lung inflammation and destructive alveolar remodeling. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors primarily expressed by diverse lung cells. RAGE expression increases following cigarette smoke exposure and expression is elevated in the lungs of patients with COPD. RAGE is responsible in part for inducing pro-inflammatory signaling pathways that culminate in expression and secretion of several cytokines, chemokines, enzymes, and other mediators. In the current review, new transgenic mouse models that conditionally over-express RAGE in pulmonary epithelium are discussed. When RAGE is over-expressed throughout embryogenesis, apoptosis in the peripheral lung causes severe lung hypoplasia. Interestingly, apoptosis in RAGE transgenic mice occurs via conserved apoptotic pathways also known to function in advanced stages of COPD. RAGE over-expression in the adult lung models features of COPD including pronounced inflammation and loss of parenchymal tissue. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of COPD.
                Bookmark

                Author and article information

                Contributors
                a.faiz@umcg.nl
                m.van.den.berge@umcg.nl
                c.j.vermeulen@umcg.nl
                n.h.t.ten.hacken@umcg.nl
                v.guryev@umcg.nl
                +31 (0)50 3613178 , s.d.pouwels@umcg.nl
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                10 April 2019
                10 April 2019
                2019
                : 20
                : 70
                Affiliations
                [1 ]ISNI 0000 0004 0407 1981, GRID grid.4830.f, Department of Pathology & Medical Biology, University Medical Center Groningen, , University of Groningen, ; Hanzeplein 1, 9713 GZ Groningen, The Netherlands
                [2 ]ISNI 0000 0004 0407 1981, GRID grid.4830.f, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, , Univesity of Groningen, ; Hanzeplein 1, 9713 GZ Groningen, The Netherlands
                [3 ]ISNI 0000 0004 0407 1981, GRID grid.4830.f, Department of Pulmonary Diseases, University Medical Center Groningen, , University of Groningen, ; Groningen, The Netherlands
                [4 ]ISNI 0000 0004 0407 1981, GRID grid.4830.f, European Research Institute for the Biology of Ageing, , University of Groningen, ; Groningen, The Netherlands
                Author information
                http://orcid.org/0000-0001-7345-8061
                Article
                1038
                10.1186/s12931-019-1038-6
                6456980
                30971245
                e806bc28-4e60-416f-a1ba-e02bd064ab76
                © 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
                : 24 October 2018
                : 29 March 2019
                Funding
                Funded by: Netherlands Lung Foundation
                Award ID: 6.2.15.044JO
                Award Recipient :
                Funded by: Noordelijke CARA Stichting
                Award ID: 2016/01
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004330, GlaxoSmithKline;
                Categories
                Letter to the Editor
                Custom metadata
                © The Author(s) 2019

                Respiratory medicine
                cigarette smoking,copd,rage,ager,alternative splicing
                Respiratory medicine
                cigarette smoking, copd, rage, ager, alternative splicing

                Comments

                Comment on this article