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      Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach

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          Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug.

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          Most cited references 45

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          Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

           Peter Barnes (2013)
          Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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            Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction.

            Chronic obstructive pulmonary disease is a leading global cause of morbidity and mortality that is characterised by inexorable deterioration of small airways obstruction with emphysema associated with cellular inflammation and structural remodelling. Other features include apoptosis as well as proliferation of cells, and both tissue repair and lack of tissue repair. Metalloprotease release, together with that of apoptotic factors, may underlie the emphysema, and, conversely, fibrosis of the small airways may be accounted for by the effects of growth factor activation. In advanced disease, influential factors include the development of autoimmunity, with activation of dendritic cells and T-helper cells of both type 1 and 2, and the senescence response. An inability of macrophages to ingest apoptosed cells and bacteria may exacerbate inflammatory responses. Systemic inflammation with concomitant cardiovascular disease and metabolic syndrome may reflect the effect of cigarette smoke on nonpulmonary cells. Corticosteroid resistance may be secondary to oxidative stress mechanisms, such as inactivation of histone deacetylases. The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes. Treatments may be targeted to patients with specific mechanisms.
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              The sentinel role of the airway epithelium in asthma pathogenesis.

              The adoption of the concept that asthma is primarily a disease most frequently associated with elaboration of T-helper 2 (Th2)-type inflammation has led to the widely held concept that its origins, exacerbation, and persistence are allergen driven. Taking aside the asthma that is expressed in non-allergic individuals leaves the great proportion of asthma that is associated with allergy (or atopy) and that often has its onset in early childhood. Evidence is presented that asthma is primarily an epithelial disorder and that its origin as well as its clinical manifestations have more to do with altered epithelial physical and functional barrier properties than being purely linked to allergic pathways. In genetically susceptible individuals, impaired epithelial barrier function renders the airways vulnerable to early life virus infection, and this in turn provides the stimulus to prime immature dendritic cells toward directing a Th2 response and local allergen sensitization. Continued epithelial susceptibility to environmental insults such as viral, allergen, and pollutant exposure and impaired repair responses leads to asthma persistence and provides the mediator and growth factor microenvironment for persistence of inflammation and airway wall remodeling. Increased deposition of matrix in the epithelial lamina reticularis provides evidence for ongoing epithelial barrier dysfunction, while physical distortion of the epithelium consequent upon repeated bronchoconstriction provides additional stimuli for remodeling. This latter response initially serves a protective function but, if exaggerated, may lead to fixed airflow obstruction associated with more severe and chronic disease. Dual pathways in the origins, persistence, and progression of asthma help explain why anti-inflammatory treatments fail to influence the natural history of asthma in childhood and only partially does so in chronic severe disease. Positioning the airway epithelium as fundamental to the origins and persistence of asthma provides a rationale for pursuit of therapeutics that increase the resistance of the airways to environmental insults rather than concentrating all effort on suppressing inflammation. © 2011 John Wiley & Sons A/S.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                23 January 2017
                : 11
                : 265-272
                [1 ]Department of Health Science, University of Catanzaro, Catanzaro
                [2 ]Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende
                [3 ]Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
                [4 ]Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
                Author notes
                Correspondence: Bruno D’Agostino, Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 115, 80138 Naples, Italy, Tel +39 81 566 5882, Email bruno.dagostino@ 123456unina2.it

                These authors contributed equally to this work

                © 2017 Gallelli et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). 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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