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 (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-gamma, 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.

• Weissmann, N.
• Sydykov, A.
• Kalwa, H.
• Storch, U.
• Fuchs, B.
• Mederos y Schnitzler, M.
• Brandes, R. P.
• Grimminger, F.
• Meissner, M.
• Freichel, M.
• Offermanns, S.
• Veit, F.
• Pak, O.
• Krause, K. H.
• Schermuly, R. T.
• Brewer, A. C.
• Schmidt, H. H.
• Seeger, W.
• Shah, A. M.
• Gudermann, T.
• Ghofrani, H. A.
• Dietrich, A.