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      Cytokine–Ion Channel Interactions in Pulmonary Inflammation

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          The lungs conceptually represent a sponge that is interposed in series in the bodies’ systemic circulation to take up oxygen and eliminate carbon dioxide. As such, it matches the huge surface areas of the alveolar epithelium to the pulmonary blood capillaries. The lung’s constant exposure to the exterior necessitates a competent immune system, as evidenced by the association of clinical immunodeficiencies with pulmonary infections. From the in utero to the postnatal and adult situation, there is an inherent vital need to manage alveolar fluid reabsorption, be it postnatally, or in case of hydrostatic or permeability edema. Whereas a wealth of literature exists on the physiological basis of fluid and solute reabsorption by ion channels and water pores, only sparse knowledge is available so far on pathological situations, such as in microbial infection, acute lung injury or acute respiratory distress syndrome, and in the pulmonary reimplantation response in transplanted lungs. The aim of this review is to discuss alveolar liquid clearance in a selection of lung injury models, thereby especially focusing on cytokines and mediators that modulate ion channels. Inflammation is characterized by complex and probably time-dependent co-signaling, interactions between the involved cell types, as well as by cell demise and barrier dysfunction, which may not uniquely determine a clinical picture. This review, therefore, aims to give integrative thoughts and wants to foster the unraveling of unmet needs in future research.

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          Most cited references 460

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          Making sense of latent TGFbeta activation.

          TGFbeta is secreted as part of a latent complex that is targeted to the extracellular matrix. A variety of molecules, 'TGFbeta activators,' release TGFbeta from its latent state. The unusual temporal discontinuity of TGFbeta synthesis and action and the panoply of TGFbeta effects contribute to the interest in TGF-beta. However, the logical connections between TGFbeta synthesis, storage and action are obscure. We consider the latent TGFbeta complex as an extracellular sensor in which the TGFbeta propeptide functions as the detector, latent-TGFbeta-binding protein (LTBP) functions as the localizer, and TGF-beta functions as the effector. Such a view provides a logical continuity for various aspects of TGFbeta biology and allows us to appreciate TGFbeta biology from a new perspective.
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            Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

            Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-α, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage.
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              Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.

              The amiloride-sensitive epithelial sodium channel constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is upregulated by vasopressin and aldosterone, hormones involved in the maintenance of sodium balance, blood volume and blood pressure. We have identified the primary structure of the alpha-subunit of the rat epithelial sodium channel by expression cloning in Xenopus laevis oocytes. An identical subunit has recently been reported. Here we identify two other subunits (beta and gamma) by functional complementation of the alpha-subunit of the rat epithelial Na+ channel. The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                04 January 2018
                : 8
                1Internal Medicine and Pneumology, Lindenhofspital , Bern, Switzerland
                2Internal Medicine V – Pneumology, Allergology, Respiratory and Environmental Medicine, Faculty of Medicine, Saarland University , Saarbrücken, Germany
                3Lungen- und Atmungsstiftung Bern , Bern, Switzerland
                4Internal Medicine, Sonnenhofspital Bern , Bern, Switzerland
                5Faculty of Medicine, Institute of Immunology, University of Regensburg , Regensburg, Germany
                6Paediatric Visceral Surgery, Universitäts-Kinderspital Zürich , Zürich, Switzerland
                7Department of Pharmacology and Toxicology, Vascular Biology Center, Medical College of Georgia , Augusta, GA, United States
                8Novartis Institutes for Biomedical Research, Translational Clinical Oncology, Novartis Pharma AG , Basel, Switzerland
                Author notes

                Edited by: Niccolo Terrando, Duke University, United States

                Reviewed by: Gene Thomas Yocum, Columbia University, United States; Michael Wilson, Imperial College London, United Kingdom

                *Correspondence: Jürg Hamacher, hamacher@

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Copyright © 2018 Hamacher, Hadizamani, Borgmann, Mohaupt, Männel, Moehrlen, Lucas and Stammberger.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 11, Tables: 3, Equations: 0, References: 517, Pages: 45, Words: 40528


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