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      Nitric Oxide and Biological Mediators in Pediatric Chronic Rhinosinusitis and Asthma

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          Abstract

          Background: In the context of the so-called unified airway theory, chronic rhinosinusitis (CRS) and asthma may coexist. The inflammation underlying these conditions can be studied through the aid of biomarkers. Main body: We described the main biological mediators that have been studied in pediatric CRS and asthma, and, according to the available literature, we reported their potential role in the diagnosis and management of these conditions. As for CRS, we discussed the studies that investigated nasal nitric oxide (nNO), pendrin, and periostin. As for asthma, we discussed the role of fractional exhaled nitric oxide (feNO), the role of periostin, and that of biological mediators measured in exhaled breath condensate (EBC) and exhaled air (volatile organic compounds, VOCs). Conclusion: Among non-invasive biomarkers, nNO seems the most informative in CRS and feNO in asthma. Other biological mediators seem promising, but further studies are needed before they can be applied in clinical practice.

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          Most cited references132

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          Asthma

          Asthma-one of the most common chronic, non-communicable diseases in children and adults-is characterised by variable respiratory symptoms and variable airflow limitation. Asthma is a consequence of complex gene-environment interactions, with heterogeneity in clinical presentation and the type and intensity of airway inflammation and remodelling. The goal of asthma treatment is to achieve good asthma control-ie, to minimise symptom burden and risk of exacerbations. Anti-inflammatory and bronchodilator treatments are the mainstay of asthma therapy and are used in a stepwise approach. Pharmacological treatment is based on a cycle of assessment and re-evaluation of symptom control, risk factors, comorbidities, side-effects, and patient satisfaction by means of shared decisions. Asthma is classed as severe when requiring high-intensity treatment to keep it under control, or if it remains uncontrolled despite treatment. New biological therapies for treatment of severe asthma, together with developments in biomarkers, present opportunities for phenotype-specific interventions and realisation of more personalised treatment. In this Seminar, we provide a clinically focused overview of asthma, including epidemiology, pathophysiology, clinical diagnosis, asthma phenotypes, severe asthma, acute exacerbations, and clinical management of disease in adults and children older than 5 years. Emerging therapies, controversies, and uncertainties in asthma management are also discussed.
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            Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals.

            Subepithelial fibrosis is a cardinal feature of bronchial asthma. Collagen I, III, and V; fibronectin; and tenascin-C are deposited in the lamina reticularis. Extensive evidence supports the pivotal role of IL-4 and IL-13 in subepithelial fibrosis; however, the precise mechanism remains unclear. We have previously identified the POSTN gene encoding periostin as an IL-4/IL-13-inducible gene in bronchial epithelial cells. Periostin is thought to be an adhesion molecule because it possesses 4 fasciclin I domains. We explore the possibility that periostin is involved in subepithelial fibrosis in bronchial asthma. We analyzed induction of periostin in lung fibroblasts by IL-4 or IL-13. We next analyzed expression of periostin in patients with asthma and in ovalbumin-sensitized and ovalbumin-inhaled mice. Furthermore, we examined the binding ability of periostin to other extracellular matrix proteins. Both IL-4 and IL-13 induced secretion of periostin in lung fibroblasts independently of TGF-beta. Periostin colocalized with other extracellular matrix proteins involved in subepithelial fibrosis in both asthma patients and ovalbumin-sensitized and ovalbumin-inhaled wild-type mice, but not in either IL-4 or IL-13 knockout mice. Periostin had an ability to bind to fibronectin, tenascin-C, collagen V, and periostin itself. Periostin secreted by lung fibroblasts in response to IL-4 and/or IL-13 is a novel component of subepithelial fibrosis in bronchial asthma. Periostin may contribute to this process by binding to other extracellular matrix proteins. Periostin induced by IL-4/IL-13 shows promise in inhibiting subepithelial fibrosis in bronchial asthma.
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              Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.

              Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by T(H)2 cytokines in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. We measured fraction of exhaled nitric oxide (Feno), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV(1), 60% of predicted value; mean Asthma Control Questionnaire [ACQ] score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, Feno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia (P = .007). Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting T(H)2 inflammation. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                25 October 2019
                November 2019
                : 8
                : 11
                : 1783
                Affiliations
                Women’s and Children’s Health Department, University of Padova, via Giustiniani 2, 35128 Padova, Italy
                Author notes
                [* ]Correspondence: ferrarovalentina@ 123456hotmail.com ; Tel.: +39-0498213505
                Article
                jcm-08-01783
                10.3390/jcm8111783
                6912805
                31731479
                b7c1914e-d636-4031-8129-2d12daf28447
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 07 September 2019
                : 23 October 2019
                Categories
                Review

                nitric oxide,biological mediators,pediatric rhinosinusitis,pediatric asthma

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