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      Airway remodeling in asthma: what really matters

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          Abstract

          Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and “endotyped” human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

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          Type 2 inflammation in asthma--present in most, absent in many.

          John Fahy (2015)
          Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation--into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes)--has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.
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            Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.

            Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients. Nevertheless, despite its enormous impact on human health, there are currently no approved treatments that directly target the mechanism(s) of fibrosis. The primary goals of this Review series on fibrotic diseases are to discuss some of the major fibroproliferative diseases and to identify the common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.
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              Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.

              Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4(+) Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden-like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses.
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                Author and article information

                Contributors
                hfehrenbach@fz-borstel.de
                Journal
                Cell Tissue Res
                Cell Tissue Res
                Cell and Tissue Research
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0302-766X
                1432-0878
                11 February 2017
                11 February 2017
                2017
                : 367
                : 3
                : 551-569
                Affiliations
                [1 ]ISNI 0000 0004 0493 9170, GRID grid.418187.3, , Division of Experimental Pneumology, Priority Area Asthma & Allergy, Research Center Borstel, Leibniz Center for Medicine and Biosciences, ; Parkallee 1-40, 23845 Borstel, Germany
                [2 ]Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Großhansdorf, Kiel, Lübeck, Germany
                [3 ]ISNI 0000 0004 0493 9170, GRID grid.418187.3, , Junior Research Group of Invertebrate Models, Priority Area Asthma & Allergy, Research Center Borstel, Leibniz Center for Medicine and Biosciences, ; Parkallee 1-40, 23845 Borstel, Germany
                [4 ]Leibniz-ScienceCampus Evolutionary Medicine of the Lung (EvoLUNG), Kiel, Germany
                [5 ]ISNI 0000 0004 0493 9170, GRID grid.418187.3, , Junior Research Group of Asthma Mouse Models, Priority Area Asthma & Allergy, Research Center Borstel, Leibniz Center for Medicine and Biosciences, ; Parkallee 1-40, 23845 Borstel, Germany
                Article
                2566
                10.1007/s00441-016-2566-8
                5320023
                28190087
                94d92885-f781-4be1-b926-5f0db3839990
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 20 October 2016
                : 21 December 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: German Center of Lung Research, Airway Research Ce
                Funded by: FundRef http://dx.doi.org/10.13039/501100001664, Leibniz-Gemeinschaft;
                Award ID: Leibniz-WissenschaftsCampus EvoLUNG
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Cluster of Excellence “Inflammation at Interfaces”
                Categories
                Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2017

                Molecular medicine
                asthma,airway remodeling,airway pathology
                Molecular medicine
                asthma, airway remodeling, airway pathology

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