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      Relationship of Serum Levels of IL-17, IL-18, TNF- α, and Lung Function Parameters in Patients with COPD, Asthma-COPD Overlap, and Bronchial Asthma

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          Abstract

          Determination of markers of systemic inflammation is one of the important directions in the study of pathogenesis and improvement of diagnosis of chronic obstructive pulmonary disease (COPD), asthma-COPD overlap (ACO), and bronchial asthma (BA). The aim of our work was a comparative study of the features of changes in serum levels of IL-17, IL-18, and TNF- α in patients with COPD, ACO, and BA with various severity of the disease, as well as evaluation of the relationship between the level of these cytokines and lung ventilation function. A total of 147 patients with COPD ( n = 58), ACO ( n = 57), and BA ( n = 32) during a stable period have been examined in this study. The control group included 21 healthy nonsmokers with similar sex-age indicators. Serum levels of IL-17, IL-18, and TNF- α were determined by ELISA. The concentrations of these cytokines in the circulation in the studied patients with COPD, ACO, and BA were higher than those in healthy nonsmokers ( p ≤ 0.001). IL-17 and IL-18 levels in the blood serum were comparable in all examined patients. The mean TNF- α concentrations in the circulation in COPD and ACO were significantly higher than those in BA ( p < 0.001). In patients with COPD, the levels of IL-17 and TNF- α increased progressively against the background of a decrease in numerous spirometric indicators, which allows us to consider these cytokines as systemic biomarkers of disease severity. In BA, the inverse correlations between the level of IL-17 and FEV1/FVC (%) and FEV1 have been found. In patients with ACO, the increase in IL-18 levels was associated with a decrease in FEV1 and TNF- α with FEV1/FVC (%). These findings indicate that IL-17, IL-18, and TNF- α can participate in the mechanisms of systemic inflammation and the genesis of disorders of airway obstruction in COPD, AСO, and BA. An increase in the levels of IL-17 and TNF- α may be associated with impaired bronchial patency in COPD and BA. The established associations of the IL-18 concentration in the blood serum and FEV1 only in patients with ACO allow using the level of IL-18 as a potential marker of the degree of impaired airway obstruction in this disease.

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          Most cited references31

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          Interleukin‐18: Biological properties and role in disease pathogenesis

          Summary Initially described as an interferon (IFN)γ‐inducing factor, interleukin (IL)‐18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL‐17‐producing γδ T cells and macrophage activation. IL‐18, a member of the IL‐1 family, is similar to IL‐1β for being processed by caspase 1 to an 18 kDa‐biologically active mature form. IL‐18 binds to its specific receptor (IL‐18Rα, also known as IL‐1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL‐18Rβ chain. IL‐18 then uses the same signaling pathway as IL‐1 to activate NF‐kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL‐18 also binds to the circulating high affinity IL‐18 binding protein (BP), such as only unbound free IL‐18 is active. IL‐18Rα may also bind IL‐37, another member of the IL‐1 family, but in association with the negative signaling chain termed IL‐1R8, which transduces an anti‐inflammatory signal. IL‐18BP also binds IL‐37 and this acts as a sink for the anti‐inflammatory properties of IL‐37. There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain‐of‐function mutations, IL‐18 circulates in the range of tens of nanograms/mL. HS is treated with the IL‐1 Receptor antagonist (anakinra) but also specifically with IL‐18BP. Systemic juvenile idiopathic arthritis or adult‐onset Still's disease are also characterized by high serum IL‐18 concentrations and are treated by IL‐18BP.
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            Cellular and molecular mechanisms of asthma and COPD.

            Asthma and chronic obstructive pulmonary disease (COPD) both cause airway obstruction and are associated with chronic inflammation of the airways. However, the nature and sites of the inflammation differ between these diseases, resulting in different pathology, clinical manifestations and response to therapy. In this review, the inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted. These differences account for the differences in clinical manifestations of asthma and COPD and their response to therapy. Although asthma and COPD are usually distinct, there are some patients who show an overlap of features, which may be explained by the coincidence of two common diseases or distinct phenotypes of each disease. It is important to better understand the underlying cellular and molecular mechanisms of asthma and COPD in order to develop new treatments in areas of unmet need, such as severe asthma, curative therapy for asthma and effective anti-inflammatory treatments for COPD.
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              IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction

              Emerging evidence suggests that the TH17 subset of αβ T cells contributes to the development of allergic asthma. In this study we found that mice lacking αvβ8 on dendritic cells failed to generate TH17 cells in the lung and were protected from AHR in response to house dust mite and ovalbumin sensitization and challenge. Because loss of TH17 cells inhibited airway narrowing without obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of TH17 cytokines on mouse and human airway smooth muscle function. IL-17A enhanced contractile force generation through a NF-κB/RhoA/ROCK2 signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after OVA sensitization and challenge, and the diminished contraction of tracheal rings from these mice was reversed by IL-17A. These data indicate that IL-17A produced by TH17 cells contributes to allergen-induced AHR through direct effects on airway smooth muscle.
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                Author and article information

                Contributors
                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi
                0962-9351
                1466-1861
                2020
                12 July 2020
                : 2020
                : 4652898
                Affiliations
                1Kazan Federal University, Kremlyovskaya St., 18, Kazan 420000, Russia
                2Federal State Budgetary Educational Institution of Higher Education “Privolzhsky Research Medical University, Minin and Pozharsky Square 10/1, Nizhny Novgorod 603005, Russia
                3Pulmonology Scientific Research Institute under FMBA of Russia, Orekhovyy Bul'var 28, Moscow 115682, Russia
                4State Health Facility “City Clinical Hospital No. 5”, St. Nesterova, 34, Nizhny Novgorod 603005, Russia
                5Instituto Politecnico Nacional, Av. Juan de Dios Bátiz, Esq. Miguel Othón de Mendizábal, Col. Nueva Industrial Vallejo, Alcaldía Gustavo A. Madero, 07738 Mexico City, Mexico
                6Centro de Investigación en Computación, Instituto Politécnico Nacional (CIC-IPN), Av. Juan de Dios Bátiz, Esq. Miguel Othón de Mendizábal S/N, Gustavo A. Madero, 07738 Mexico City, Mexico
                7Department of Pediatrics, Medical Institute, Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russia
                Author notes

                Academic Editor: Mirella Giovarelli

                Author information
                https://orcid.org/0000-0002-5582-5814
                https://orcid.org/0000-0002-1769-3670
                https://orcid.org/0000-0001-6453-0017
                https://orcid.org/0000-0001-8593-1098
                https://orcid.org/0000-0001-9730-8308
                https://orcid.org/0000-0003-4692-2564
                https://orcid.org/0000-0003-3452-8666
                https://orcid.org/0000-0003-0241-7902
                Article
                10.1155/2020/4652898
                7372292
                32733164
                30aaa49c-90c8-4fb8-8a20-e159f552eb8c
                Copyright © 2020 Nailya Kubysheva et al.

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

                History
                : 5 October 2019
                : 26 December 2019
                : 21 January 2020
                Funding
                Funded by: Kazan Federal University
                Categories
                Research Article

                Immunology
                Immunology

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