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

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 Theo Schermuly, Alison C. Brewer, Harald H. H. W. Schmidt, Werner Seeger, Ajay M. Shah, Thomas GudermannHossein Ardeschir Ghofrani, Alexander Dietrich

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

141 Citations (Web of Science)

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-?, 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.
Original languageEnglish
Pages (from-to)649
JournalNature Communications
Volume3
DOIs
Publication statusPublished - Jan 2012

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