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

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 dinucleotid
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 (Nox2y/−) 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 Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− 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.
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Author:Norbert Weissmann, Akylbek Sydykov, Hermann Kalwa, Ursula Storch, Beate Fuchs, Michael Mederos y Schnitzler, Ralf Peter Louis Brandes, Friedrich Grimminger, Marcel Meissner, Marc Freichel, Stefan Offermanns, Florian Veit, Oleg Pak, Karl-Heinz Krause, Ralph T. Schermuly, Alison C. Brewer, Harald H.H.W. Schmidt, Werner Seeger, Ajay M. Shah, Thomas Gudermann, Hossein A. Ghofrani, Alexander Dietrich
URN:urn:nbn:de:hebis:30:3-258020
DOI:http://dx.doi.org/10.1038/ncomms1660
ISSN:2041-1723
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=22337127
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2012/01/31
Date of first Publication:2012/01/31
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2012/08/30
Volume:3
Issue:Article number: 649
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen

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