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 dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potent...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
31 January 2012
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| In: |
Nature Communications
Year: 2012, Volume: 3 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms1660 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1038/ncomms1660 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/ncomms1660 
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| Author Notes: | 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 |
| Summary: | 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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| Item Description: | Gesehen am 05.10.2018 |
| Physical Description: | Online Resource |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms1660 |