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

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 7

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P-selectin expression in lung capillaries. Each inhibitor was infused fo...
P-selectin expression in lung capillaries. Each inhibitor was infused for 20 minutes prior to imaging. (a) Images of single capillaries show immunofluorescence of P-selectin at varying PLA in the absence (left pair) and presence (right pair) of the indicated inhibitors. Arrows pointing to the same EC in the same capillary show fluorescence increase. Images show fluorescence intensity as gray levels. Bar = 10 μm. (b) Responses to the indicated PLA are shown for untreated capillaries and capillaries given mitochondrial blockers (1 μM rotenone or 400 nM FCCP). Responses are after 10 minutes of pressure elevation. *P < 0.05 compared with control; mean ± SE; n = 3 for each group. Inset shows responses to a 5-minute H2O2 infusion (100 μM) in the absence of any agents (UN) and in the presence of rotenone and FCCP (2 μM). (c) Responses to PLA of 15 cmH2O shown as difference from baseline in untreated capillaries (CT) and in capillaries treated with ebselen (EB, 100 μM), NAC (NA, 10 mM), PEG-catalase (PC, 100 U/ml), diphenyleneiodonium (DP, 10 μM), and allopurinol (AL, 100 μM). *P < 0.05 compared with control; mean ± SE; n = 3 for each group.