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

H Ichimura, K Parthasarathi, S Quadri… - The Journal of …, 2003 - Am Soc Clin Investig
H Ichimura, K Parthasarathi, S Quadri, AC Issekutz, J Bhattacharya
The Journal of clinical investigation, 2003Am Soc Clin Investig
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 Ca2+ oscillations that triggered increases in the amplitude of mitochondrial Ca2+ …
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 Ca2+ oscillations that triggered increases in the amplitude of mitochondrial Ca2+ oscillations and in reactive oxygen species (ROS) production. Responses to blockers of the Ca2+ oscillations and of mitochondrial electron transport indicated that the ROS production was Ca2+ 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 Ca2+ 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.
The Journal of Clinical Investigation