title: Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice.
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.
authors.affiliation: Department of Internal Medicine II/V, University of Giessen Lung Center, Klinikstrasse 36, 35392 Giessen, Germany. Norbert.Weissmann@innere.med.uni-giessen.de
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Akylbek
authors.initials: A
authors.lastname: Sydykov
authors.forename: Hermann
authors.initials: H
authors.lastname: Kalwa
authors.forename: Ursula
authors.initials: U
authors.lastname: Storch
authors.forename: Beate
authors.initials: B
authors.lastname: Fuchs
authors.forename: Michael
authors.initials: M
authors.lastname: Mederos y Schnitzler
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Marcel
authors.initials: M
authors.lastname: Meissner
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Florian
authors.initials: F
authors.lastname: Veit
authors.forename: Oleg
authors.initials: O
authors.lastname: Pak
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004487:Edema / Q000473:pathology / Q000628:therapy*; D042783:Endothelial Cells / Q000166:cytology; D017353:Gene Deletion; D008168:Lung / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D010539:Permeability; D051966:Phospholipase C gamma / Q000378:metabolism; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury; D050052:TRPC Cation Channels / Q000235:genetics*; D000074287:TRPC6 Cation Channel; D013997:Time Factors
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019852:Diacylglycerol Kinase; D051966:Phospholipase C gamma; D002118:Calcium