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      Endoplasmic reticulum, Golgi, and lysosomes are disorganized in lung fibroblasts from chronic obstructive pulmonary disease patients

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          Abstract

          Chronic Obstructive Pulmonary Disease ( COPD) is often caused by smoking and other stressors. This causes oxidative stress, which induces numerous changes on both the transcriptome and proteome of the cell. We aimed to examine if the endomembrane pathway, including the endoplasmic reticulum ( ER), Golgi, and lysosomes, was disrupted in fibroblasts from COPD patients as opposed to healthy ever‐smokers or never‐smokers, and if the response to stress differed. Different cellular compartments involved in the endomembrane pathway, as well as mRNA expression and apoptosis, were examined before and after the addition of stress in lung fibroblasts from never‐smokers, ever‐smokers, and patients with COPD. We found that the ER, Golgi, and lysosomes were disorganized in fibroblasts from COPD patients under baseline conditions. After a time course with ER stress inducing chemicals, changes to the phenotypes of cellular compartments in COPD patient fibroblasts were observed, and the expression of the ER stress‐induced gene ERP72 was upregulated more in the COPD patient's cells compared to ever‐smokers or never‐smokers. Lastly, a tendency of increased active Caspase‐3 was observed in COPD fibroblasts. Our results show that COPD patients have phenotypic changes in the lung fibroblasts endomembrane pathway, and respond differently to stress. Furthermore, these fibroblasts were cultured for several weeks outside the body, but they were not able to regain proper ER structure, indicating that the internal changes to the endomembrane system are permanent in smokers. This vulnerability to cellular stress might be a cause as to why some smokers develop COPD.

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          Most cited references23

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          ER stress-induced cell death mechanisms.

          The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways. © 2013.
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            Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease.

            The endoplasmic reticulum (ER) is a specialized organelle for the folding and trafficking of proteins, which is highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Alterations in the protein-folding environment cause accumulation of misfolded proteins in the ER that profoundly affect a variety of cellular signaling processes, including reduction-oxidation (redox) homeostasis, energy production, inflammation, differentiation, and apoptosis. The unfolded protein response (UPR) is a collection of adaptive signaling pathways that evolved to resolve protein misfolding and restore an efficient protein-folding environment. Production of reactive oxygen species (ROS) has been linked to ER stress and the UPR. ROS play a critical role in many cellular processes and can be produced in the cytosol and several organelles, including the ER and mitochondria. Studies suggest that altered redox homeostasis in the ER is sufficient to cause ER stress, which could, in turn, induce the production of ROS in the ER and mitochondria. Although ER stress and oxidative stress coexist in many pathologic states, whether and how these stresses interact is unknown. It is also unclear how changes in the protein-folding environment in the ER cause oxidative stress. In addition, how ROS production and protein misfolding commit the cell to an apoptotic death and contribute to various degenerative diseases is unknown. A greater fundamental understanding of the mechanisms that preserve protein folding homeostasis and redox status will provide new information toward the development of novel therapeutics for many human diseases.
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              The endoplasmic reticulum: structure, function and response to cellular signaling

              The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
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                Author and article information

                Contributors
                ellen.tufvesson@med.lu.se
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                27 February 2018
                March 2018
                : 6
                : 5 ( doiID: 10.1002/phy2.2018.6.issue-5 )
                : e13584
                Affiliations
                [ 1 ] Department of Clinical Sciences Lund, Respiratory Medicine and Allergology Lund University Lund Sweden
                [ 2 ] Department of Experimental Medical Science Lung Biology Lund University Lund Sweden
                Author notes
                [*] [* ] Correspondence

                Ellen Tufvesson, Department of Clinical Sciences, Lund, Respiratory Medicine and Allergology, Lund University, BMC, D12, 221 84 Lund, Sweden.

                Tel: +46 46 222 7828

                E‐mail: ellen.tufvesson@ 123456med.lu.se

                Article
                PHY213584
                10.14814/phy2.13584
                5827558
                29484832
                01e2c578-6fad-41f6-a8e8-42a5d63fdf92
                © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 November 2017
                : 18 December 2017
                : 26 December 2017
                Page count
                Figures: 6, Tables: 2, Pages: 11, Words: 5957
                Funding
                Funded by: Swedish Heart‐Lung Foundation
                Funded by: Swedish Research Council
                Funded by: Evy and Gunnar Sandberg's Foundation
                Funded by: Crafoord Foundation
                Funded by: Royal Physiographic Society in Lund
                Categories
                Respiratory Conditions Disorder and Diseases
                Lung
                Membrane Physiology
                Toxins, Pollutants and Chemical Agents
                Original Research
                Original Research
                Custom metadata
                2.0
                phy213584
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:27.02.2018

                chronic obstructive pulmonary disease,endoplasmic reticulum,endoplasmic reticulum stress response,golgi,lung fibroblast

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