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Related Experiment Videos

Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways.

Raja-Elie E Abdulnour1, Xinqi Peng, Jay H Finigan

  • 1Division of Pulmonary and Critical Care Medicine, Bloomberg School of Public Health, Baltimore, Maryland, USA.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|April 25, 2006
PubMed
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Mechanical ventilation increases xanthine oxidoreductase (XOR) activity, contributing to ventilator-induced lung injury (VILI). Inhibiting XOR reduces lung injury, highlighting its critical role in VILI pathogenesis.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Biochemistry

Background:

  • Xanthine oxidoreductase (XOR) generates reactive oxygen species, implicating it in acute lung injury.
  • Ventilator-induced lung injury (VILI) is a significant complication of mechanical ventilation.

Purpose of the Study:

  • To investigate the role of XOR in the development of VILI.
  • To determine the effect of mechanical stress on XOR activity in lung tissue and pulmonary endothelial cells.
  • To examine the therapeutic potential of XOR inhibition in VILI.

Main Methods:

  • Mechanical ventilation (MV) was applied to mice at high tidal volumes, with subsequent measurement of lung XOR activity and expression.
  • Pulmonary vascular leakage was assessed using Evans blue dye extravasation and bronchoalveolar lavage protein concentration.

Related Experiment Videos

  • Rat pulmonary microvascular endothelial cells (RPMECs) were subjected to cyclic stretch to mimic mechanical stress, and XOR activity was measured.
  • The effects of the XOR inhibitor allopurinol and specific MAP kinase inhibitors were evaluated.

    • Main Results:

    • MV significantly increased lung XOR activity without altering XOR expression.
    • Mechanical ventilation led to increased pulmonary vascular leakage, which was significantly reduced by allopurinol.
    • Cyclic stretch of RPMECs increased intracellular XOR activity and induced MAP kinase phosphorylation (p38, ERK1/2, ERK5).
    • MAP kinase inhibitors abrogated the stretch-induced increase in XOR activity in RPMECs.

    Conclusions:

    • Mechanical stress significantly increases XOR enzymatic activity through p38 MAP kinase and ERK activation.
    • XOR plays a critical role in the pathogenesis of pulmonary edema associated with VILI.
    • Targeting XOR may represent a therapeutic strategy for mitigating VILI.