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

被引：159

作者：

Weissmann, Norbert ^{[1
]}

Sydykov, Akylbek ^{[1
]}

Kalwa, Hermann ^{[2
]}

Storch, Ursula ^{[3
]}

Fuchs, Beate ^{[1
]}

Mederos y Schnitzler, Michael ^{[3
]}

Brandes, Ralf P. ^{[4
]}

Grimminger, Friedrich ^{[1
]}

Meissner, Marcel ^{[5
]}

Freichel, Marc ^{[5
]}

Offermanns, Stefan ^{[6
]}

Veit, Florian ^{[1
]}

Pak, Oleg ^{[1
]}

Krause, Karl-Heinz ^{[7
]}

Schermuly, Ralph T. ^{[1
]}

Brewer, Alison C. ^{[8
]}

Schmidt, Harald H. H. W. ^{[9
]}

Seeger, Werner ^{[1
]}

Shah, Ajay M. ^{[8
]}

Gudermann, Thomas ^{[3
]}

Ghofrani, Hossein A. ^{[1
]}

Dietrich, Alexander ^{[3
]}

机构：

[1] UGLC, Dept Internal Med 2 5, D-35392 Giessen, Germany

[2] Univ Marburg, Sch Med, Inst Pharmacol & Toxicol, D-35033 Marburg, Germany

[3] Univ Munich, Walther Straub Inst Pharmacol & Toxicol, D-80336 Munich, Germany

[4] Goethe Univ Frankfurt, Fac Med, Vasc Res Ctr, D-60596 Frankfurt, Germany

[5] Univ Saarland, Fac Med, D-66424 Homburg, Germany

[6] Max Planck Inst Heart & Lung Res, Dept Pharmacol, D-61231 Bad Nauheim, Germany

[7] Ctr Med Univ Geneva, Geneva Fac Med, CH-1211 Geneva 4, Switzerland

[8] Kings Coll London, British Heart Fdn Ctr, Div Cardiovasc, London SE5 9PJ, England

[9] Dept Pharmacol & Toxicol, NL-6200 MD Maastricht, Netherlands

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

关键词：

ALVEOLAR MACROPHAGE; SURFACTANT TREATMENT; OXIDATIVE STRESS; CA2+ ENTRY; INJURY; DEPLETION; NEUTROPHILS; EXPRESSION; PRESSURE; KINASE;

D O I：

10.1038/ncomms1660

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 Ca2+ 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.

引用

页数：10

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