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

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.

Journal

Journal ID (nlm-ta): Nat Commun

Title: Nature Communications

Publisher: Nature Pub. Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 31 January 2012

Volume: 3

Page: 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

[a ] Norbert.Weissmann@ 123456innere.med.uni-giessen.de

[b ] alexander.dietrich@ 123456lrz.uni-muenchen.de

Article

Publisher Item ID: ncomms1660

DOI: 10.1038/ncomms1660

PMC ID: 3272568

PubMed ID: 22337127

SO-VID: 7e244287-319b-4695-b9ae-2784a1115933

Copyright statement: Copyright © 2012, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

License:

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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Subject: Article