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

• Verfasst von: Weißmann, Norbert [VerfasserIn]
• Verfasst von: Freichel, Marc [VerfasserIn]
• Titel: Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice
• Verf.angabe: Norbert Weissmann, Akylbek Sydykov, Hermann Kalwa, Ursula Storch, Beate Fuchs, Michael Mederos y Schnitzler, Ralf P. 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
• E-Jahr: 2012
• Jahr: 31 January 2012
• Umfang: 10 S.
• Teil: volume:3
• Teil: year:2012
• Teil: elocationid:649
• Teil: extent:10
• Fussnoten: Gesehen am 05.10.2018
• Titel Quelle: Enthalten in: Nature Communications
• Ort Quelle: [London] : Nature Publishing Group UK, 2010
• Jahr Quelle: 2012
• Band/Heft Quelle: 3(2012), Artikel-ID 649
• ISSN Quelle: 2041-1723
• DOI: doi:10.1038/ncomms1660
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1581594488

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 (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.