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.


  • Animals
  • Calcium/metabolism
  • Diacylglycerol Kinase/metabolism
  • Edema/pathology/*therapy
  • Endothelial Cells/cytology
  • Gene Deletion
  • Lung/*pathology
  • Membrane Glycoproteins/genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • NADPH Oxidase 2
  • NADPH Oxidases/genetics
  • Permeability
  • Phospholipase C gamma/metabolism
  • Reactive Oxygen Species
  • *Reperfusion Injury
  • TRPC Cation Channels/*genetics
  • TRPC6 Cation Channel
  • Time Factors
Publication details
DOI: 10.1038/ncomms1660
Journal: Nat Commun
Pages: 649
Work Type: Original
Access number: 22337127
See publication on PubMed