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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)691-699
Number of pages9
JournalJournal of Clinical Investigation
Volume111
Issue number5
DOIs
StatePublished - Jan 1 2003

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Oxidative Coupling
Exocytosis
P-Selectin
Mitochondria
Reactive Oxygen Species
Pressure
Lung
Endothelial Cells
Leukocyte-Adhesion Receptors
Electron Transport
Fluorescence Microscopy
Antioxidants

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. / Ichimura, Hideo; Parthasarathi, Kaushik; Quadri, Sadiqa; Issekutz, Andrew C.; Bhattacharya, Jahar.

In: Journal of Clinical Investigation, Vol. 111, No. 5, 01.01.2003, p. 691-699.

Research output: Contribution to journalArticle

Ichimura, Hideo ; Parthasarathi, Kaushik ; Quadri, Sadiqa ; Issekutz, Andrew C. ; Bhattacharya, Jahar. / Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 5. pp. 691-699.
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