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      Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice

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          Abstract

          Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase ( Nox2 y/− ) or the classical transient receptor potential channel 6 ( TRPC6 −/− ) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca 2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2 y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.

          Abstract

          The signalling cascade involved in lung ischaemia–reperfusion-induced oedema is poorly understood. Using knockout mice, Weissmann et al. propose a model in which reactive oxygen species production by endothelial NOX2 leads to phospholipase C-γ activation, DAG kinase inhibition and subsequent TRPC6 activation.

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          Most cited references42

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          TRP channels.

          The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease.
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            Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production.

            Chronic granulomatous disease (CGD) is a recessive disorder characterized by a defective phagocyte respiratory burst oxidase, life-threatening pyogenic infections and inflammatory granulomas. Gene targeting was used to generate mice with a null allele of the gene involved in X-linked CGD, which encodes the 91 kD subunit of the oxidase cytochrome b. Affected hemizygous male mice lacked phagocyte superoxide production, manifested an increased susceptibility to infection with Staphylococcus aureus and Aspergillus fumigatus and had an altered inflammatory response in thioglycollate peritonitis. This animal model should aid in developing new treatments for CGD and in evaluating the role of phagocyte-derived oxidants in inflammation.
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              Ischemia-reperfusion-induced lung injury.

              Ischemia-reperfusion-induced lung injury is characterized by nonspecific alveolar damage, lung edema, and hypoxemia occurring within 72 hours after lung transplantation. The most severe form may lead to primary graft failure and remains a significant cause of morbidity and mortality after lung transplantation. Over the past decade, better understanding of the mechanisms of ischemia-reperfusion injury, improvements in the technique of lung preservation, and the development of a new preservation solution specifically for the lung have been associated with a reduction in the incidence of primary graft failure from approximately 30 to 15% or less. Several strategies have also been introduced into clinical practice for the prevention and treatment of ischemia-reperfusion-induced lung injury with various degrees of success. However, only three randomized, double-blinded, placebo-controlled trials on ischemia-reperfusion-induced lung injury have been reported in the literature. In the future, the development of new agents and their application in prospective clinical trials are to be expected to prevent the occurrence of this potentially devastating complication and to further improve the success of lung transplantation.
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                Author and article information

                Journal
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                31 January 2012
                : 3
                : 649
                Affiliations
                [1 ]simpleDepartment of Internal Medicine II/V, University of Giessen Lung Center (UGLC) , Klinikstrasse 36, 35392 Giessen, Germany.
                [2 ]simpleInstitute of Pharmacology and Toxicology, School of Medicine, University of Marburg , Karl-von-Frisch-Street 1, 35033 Marburg, Germany.
                [3 ]simpleWalther-Straub-Institute of Pharmacology and Toxicology, University of Munich , Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.
                [4 ]simpleVascular Research Center, Medical Faculty, J.W. Goethe University Frankfurt , Theodor-Stern Kai 7, 60596 Frankfurt/Main, Germany.
                [5 ]simpleExperimental and Clinical Pharmacology, Medical Faculty, University of the Saarland, Universitätskliniken Geb. 46 , 66424 Homburg/Saar, Germany.
                [6 ]simpleDepartment of Pharmacology, Max-Planck-Institut für Herz und Lungenforschung , Ludwigsstrasse 43, 61231 Bad Nauheim, Germany.
                [7 ]simpleGeneva Faculty of Medicine, Centre Médical Universitaire , 1, rue Michel-Servet, 1211 Geneva 4, Switzerland.
                [8 ]simpleCardiovascular Division, King's College London British Heart Foundation Centre , London SE5 9PJ, UK.
                [9 ]simpleDepartment of Pharmacology and Toxicology, Universiteitssingel 50, 6229 ER Maastricht, 6200 MD Maastricht, The Netherlands.
                [10 ]These authors contributed equally to the work.
                [11 ]Present address: Institute for Pharmacology, Im Neuenheimer Feld 366, 69120 Heidelberg Germany.
                [12 ]Shared senior authorship.
                [13 ]Present address: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
                Author notes
                Article
                ncomms1660
                10.1038/ncomms1660
                3272568
                22337127
                7e244287-319b-4695-b9ae-2784a1115933
                Copyright © 2012, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

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