Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries.
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.
Ichimura
Hideo
H
Lung Biology Laboratory, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, New York 10019, USA.
Parthasarathi
Kaushik
K
Quadri
Sadiqa
S
Issekutz
Andrew C
AC
Bhattacharya
Jahar
J
D000818:Animals; D020013:Calcium Signaling; D002196:Capillaries / Q000276:immunology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000209:etiology*; D008168:Lung / Q000098:blood supply* / Q000276:immunology* / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D006861:Hydrogen Peroxide