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      5-Aza-2′-deoxycytidine protects against emphysema in mice via suppressing p16 Ink4a expression in lung tissue

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          There is a growing realization that COPD, or at least emphysema, involves several processes presenting in aging and cellular senescence. Endothelial progenitor cells (EPCs) contribute to neovascularization and play an important role in the development of COPD. The gene for p16 Ink4a is a major dominant senescence one. The aim of the present study was to observe changes in lung function, histomorphology of lung tissue, and expression of p16 Ink4a in lung tissue and bone marrow-derived EPCs in emphysematous mice induced by cigarette-smoke extract (CSE), and further to search for a potential candidate agent protecting against emphysema induced by CSE.

          Materials and methods

          An animal emphysema model was induced by intraperitoneal injection of CSE. 5-Aza-2′-deoxycytidine (5-Aza-CdR) was administered to the emphysematous mice. Lung function and histomorphology of lung tissue were measured. The p16 Ink4a protein and mRNA in EPCs and lung tissues were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction, respectively.


          CSE induced emphysema with increased p16 Ink4a expression in lung tissue and bone marrow-derived EPCs. 5-Aza-CdR partly protected against emphysema, especially in the lung-morphology profile, and partly protest against the overexpression of p16 Ink4a in EPCs and lung tissue induced by CSE.


          5-Aza-CdR partly protected against emphysema in mice via suppressing p16 Ink4a expression in EPCs and lung tissue.

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          Most cited references 62

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          Augmented Wnt signaling in a mammalian model of accelerated aging.

          The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.
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            A cell cycle regulator potentially involved in genesis of many tumor types.

            A putative tumor suppressor locus on the short arm of human chromosome 9 has been localized to a region of less than 40 kilobases by means of homozygous deletions in melanoma cell lines. This region contained a gene, Multiple Tumor Suppressor 1 (MTS1), that encodes a previously identified inhibitor (p16) of cyclin-dependent kinase 4. MTS1 was homozygously deleted at high frequency in cell lines derived from tumors of lung, breast, brain, bone, skin, bladder, kidney, ovary, and lymphocyte. Melanoma cell lines that carried at least one copy of MTS1 frequently carried nonsense, missense, or frameshift mutations in the gene. These findings suggest that MTS1 mutations are involved in tumor formation in a wide range of tissues.
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              There is increasing evidence for a close relationship between aging and chronic inflammatory diseases. COPD is a chronic inflammatory disease of the lungs, which progresses very slowly and the majority of patients are therefore elderly. We here review the evidence that accelerating aging of lung in response to oxidative stress is involved in the pathogenesis and progression of COPD, particularly emphysema. Aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death. This results from a failure of organs to repair DNA damage by oxidative stress (nonprogrammed aging) and from telomere shortening as a result of repeated cell division (programmed aging). During aging, pulmonary function progressively deteriorates and pulmonary inflammation increases, accompanied by structural changes, which are described as senile emphysema. Environmental gases, such as cigarette smoke or other pollutants, may accelerate the aging of lung or worsen aging-related events in lung by defective resolution of inflammation, for example, by reducing antiaging molecules, such as histone deacetylases and sirtuins, and this consequently induces accelerated progression of COPD. Recent studies of the signal transduction mechanisms, such as protein acetylation pathways involved in aging, have identified novel antiaging molecules that may provide a new therapeutic approach to COPD.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                30 October 2017
                : 12
                : 3149-3158
                [1 ]Intensive Care Unit
                [2 ]Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha
                [3 ]Department of Respiratory Medicine, Hunan Provincial People’s Hospital, Changsha, China
                Author notes
                Correspondence: Yan Chen, Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Nanyuangong Alley, Yuanjialing Shangquan, Furong Qu, Changsha, Hunan 410011, China, Email chenyan99727@
                © 2017 He et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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