Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries

J Clin Invest. 2003 Mar;111(5):691-9. doi: 10.1172/JCI17271.


Elevation of lung capillary pressure causes exocytosis of the leukocyte adhesion receptor P-selectin in endothelial cells (ECs), indicating that lung ECs generate a proinflammatory response to pressure-induced stress. To define underlying mechanisms, we followed the EC signaling sequence leading to P-selectin exocytosis through application of real-time, in situ fluorescence microscopy in lung capillaries. Pressure elevation increased the amplitude of cytosolic Ca(2+) oscillations that triggered increases in the amplitude of mitochondrial Ca(2+) oscillations and in reactive oxygen species (ROS) production. Responses to blockers of the Ca(2+) oscillations and of mitochondrial electron transport indicated that the ROS production was Ca(2+) dependent and of mitochondrial origin. A new proinflammatory mechanism was revealed in that pressure-induced exocytosis of P-selectin was inhibited by both antioxidants and mitochondrial inhibitors, indicating that the exocytosis was driven by mitochondrial ROS. In this signaling pathway mitochondria coupled pressure-induced Ca(2+) oscillations to the production of ROS that in turn acted as diffusible messengers to activate P-selectin exocytosis. These findings implicate mitochondrial mechanisms in the lung's proinflammatory response to pressure elevation and identify mitochondrial ROS as critical to P-selectin exocytosis in lung capillary ECs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium Signaling
  • Capillaries / immunology
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology
  • Hydrogen Peroxide / metabolism
  • Inflammation / etiology*
  • Lung / blood supply*
  • Lung / immunology*
  • Lung / metabolism
  • Membrane Potentials
  • Mitochondria / metabolism*
  • Nitric Oxide / physiology
  • Oxidation-Reduction
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*


  • Reactive Oxygen Species
  • Nitric Oxide
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Hydrogen Peroxide