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Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries
Hideo Ichimura, … , Andrew C. Issekutz, Jahar Bhattacharya
Hideo Ichimura, … , Andrew C. Issekutz, Jahar Bhattacharya
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):691-699. https://doi.org/10.1172/JCI17271.
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Article Cardiology

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

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Abstract

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.

Authors

Hideo Ichimura, Kaushik Parthasarathi, Sadiqa Quadri, Andrew C. Issekutz, Jahar Bhattacharya

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Figure 6

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Effect of pressure elevation on mitochondrial potential. Tracings are qu...
Effect of pressure elevation on mitochondrial potential. Tracings are quantifications of TMRM fluorescence from a single capillary. Capillaries were first loaded with TMRM, then given saponin (0.01%) infusion to permeabilize EC membranes. PLA was maintained at 5 cmH2O (light line) or 15 cmH2O (bold line). Response to FCCP (2 μM) was obtained at PLA of 5 cmH2O. Traces represent data replicated in four capillaries.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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