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Nat Commun. 2012 Jan 31;3:649. doi: 10.1038/ncomms1660.

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

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  • 1Department of Internal Medicine II/V, University of Giessen Lung Center, Klinikstrasse 36, 35392 Giessen, Germany. Norbert.Weissmann@innere.med.uni-giessen.de

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-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.

PMID:
22337127
[PubMed - indexed for MEDLINE]
PMCID:
PMC3272568
Free PMC Article
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