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      Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells

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          Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear.


          In this study, we attempted to investigate the influence of tiotropium on ECM production by ASMCs and the underlying mechanism.


          Tiotropium was added 30 minutes before the addition of methacholine to primary cultured human ASMCs. Protein expression was analylized by Western Blot and mRNA abundance was determined by real-time PCR.


          We found that tiotropium reduced collagen I protein expression, and the mRNA abundance of collagen I, fibronectin, and versican. β-catenin signaling was inactivated by inhibiting glycogen synthase kinase 3β (GSK3β) phosphorylation in this process. Tiotropum inhibited the amount of active β-catenin and its transcription activity. Furthermore, overexpression of active β-catenin by adenoviruses carrying the S33Y mutant resisted the suppressive effect of tiotropium on collagen I protein expression. However, silencing β-catenin by specific small interfering RNA enhanced the negative effect of tiotropium.


          These findings suggest that relaxation of ASMCs by tiotropium can prevent ECM production through β-catenin signaling.

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          Most cited references 28

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          Glycogen synthase kinase 3: a key regulator of cellular fate.

          The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified as a key regulator of insulin-dependent glycogen synthesis. GSK-3 was subsequently shown to function in a wide range of cellular processes including differentiation, growth, motility and apoptosis. Aberrant regulation of GSK-3 has been implicated in a range of human pathologies including Alzheimer's disease, non-insulin-dependent diabetes mellitus (NIDDM) and cancer. As a consequence, the regulation of GSK-3 and the therapeutic potential of GSK-3 inhibitors have become key areas of investigation. This review will focus on the mechanisms of GSK-3 regulation, with emphasis on modulation by upstream signals, control of substrate specificity and GSK-3 localisation. The details of these mechanisms will be discussed in the context of specific signalling pathways.
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            The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling.

            The determination of animal form depends on the coordination of events that lead to the morphological patterning of cells. This epigenetic view of development suggests that embryonic structures arise as a consequence of environmental influences acting on the properties of cells, rather than an unfolding of a completely genetically specified and preexisting invisible pattern. Specialized cells of developing multicellular organisms are surrounded by a complex extracellular matrix (ECM), comprised largely of different collagens, proteoglycans, and glycoproteins. This ECM is a substrate for tissue morphogenesis, lends support and flexibility to mature tissues, and acts as an epigenetic informational entity in the sense that it transduces and integrates intracellular signals via distinct cell surface receptors. Consequently, ECM-receptor interactions have a profound influence on major cellular programs including growth, differentiation, migration, and survival. In contrast to many other ECM proteins, the tenascin (TN) family of glycoproteins (TN-C, TN-R, TN-W, TN-X, and TN-Y) display highly restricted and dynamic patterns of expression in the embryo, particularly during neural development, skeletogenesis, and vasculogenesis. These molecules are reexpressed in the adult during normal processes such as wound healing, nerve regeneration, and tissue involution, and in pathological states including vascular disease, tumorigenesis, and metastasis. In concert with a multitude of associated ECM proteins and cell surface receptors that include members of the integrin family, TN proteins impart contrary cellular functions, depending on their mode of presentation (i.e., soluble or substrate-bound) and the cell types and differentiation states of the target tissues. Expression of tenascins is regulated by a variety of growth factors, cytokines, vasoactive peptides, ECM proteins, and biomechanical factors. The signals generated by these factors converge on particular combinations of cis-regulatory elements within the recently identified TN gene promoters via specific transcriptional activators or repressors. Additional complexity in regulating TN gene expression is achieved through alternative splicing, resulting in variants of TN polypeptides that exhibit different combinations of functional protein domains. In this review, we discuss some of the recent advances in TN biology that provide insights into the complex way in which the ECM is regulated and how it functions to regulate tissue morphogenesis and gene expression. Copyright 2000 Wiley-Liss, Inc.
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              Mechanisms of airway remodeling.

              Airway remodeling comprises the structural changes of airway walls, induced by repeated injury and repair processes. It is characterized by the changes of tissue, cellular, and molecular composition, affecting airway smooth muscle, epithelium, blood vessels, and extracellular matrix. It occurs in patients with chronic inflammatory airway diseases such as asthma, COPD, bronchiectasis, and cystic fibrosis. Airway remodeling is arguably one of the most intractable problems in these diseases, leading to irreversible loss of lung function. Current therapeutics can ameliorate inflammation, but there is no available therapy proven to prevent or reverse airway remodeling, although reversibility of airway remodeling is suggested by studies in animal models of disease. Airway remodeling is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the necessity for early and specific therapeutic interventions. In this review, we consider the factors that may contribute to airway remodeling and discuss the current and potential therapeutic interventions.

                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
                03 May 2018
                : 13
                : 1469-1481
                State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
                Author notes
                Correspondence: Rongchang Chen, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China, Tel +86 158 2024 3582, Fax +86 20 8306 2882, Email chenrcstatekeylab@
                © 2018 Huo 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.

                Original Research

                Respiratory medicine

                tiotropium, collagen i, β-catenin, airway smooth muscle cell


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