Weissmann, NorbertSydykov, AkylbekStorch, UrsulaFuchs, BeateSchnitzler, Michael Mederos yBrandes, Ralf P.Grimminger, FriedrichMeissner, MarcelFreichel, MarcOffermanns, StefanVeit, FlorianPak, OlegKrause, Karl-HeinzSchermuly, Ralph T.Brewer, Alison CSchmidt, Harald H.H.W.Seeger, WernerGudermann, ThomasGhofrani, Hossein A.Dietrich, AlexanderKalwa, HermannShah, Ajay Mukesh2012-04-192012Weissmann, Norbert, Akylbek Sydykov, Hermann Kalwa, Ursula Storch, Beate Fuchs, Michael Mederos y Schnitzler, Ralf P. Brandes, et al. 2012. Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice. Nature Communications 3:649.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:8603136Lung 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.en-USJournal Article2012-04-1910.1038/ncomms1660