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Volume 11 Supplement 4

Sepsis 2007

The activity of the endothelial Tie-2 receptor modulates ventilation-induced lung injury in septic mice


Patients requiring mechanical ventilation, particularly in the presence of sepsis, are at risk for ventilation-induced lung injury (VILI), which is characterized by increased pulmonary vascular permeability and inflammation. Inflammation in VILI is initiated through interactions between endothelial and inflammatory cells. The vasoprotective protein angiopoietin-1, a ligand for the endothelial-selective tyrosine kinase receptor Tie-2, has recently been recognized to play a critical role in regulating endothelial inflammation and vascular permeability. In contrast, angiopoietin-2, which binds with equal affinity, has been described as a Tie-2 antagonist, inhibiting receptor activation in response to angio-poietin-1. We therefore examined the role of the angiopoietins/Tie-2 pathway in mechanically ventilated, septic mice.

Materials and methods

Wild-type (WT) or Tie-2+/- mice were anaesthetized and sepsis was induced by cecum ligation and puncture (CLP). After 24 hours, animals were ventilated for 6 hours to induce VILI. Animals were ventilated in a pressure-controlled mode, at a fractional inspired oxygen concentration of 0.5, an inspiration to expiration ratio of 1:2, a peak inspiratory pressure of 14 cmH2O and a positive end-expiratory pressure of 2 cmH2O. Animals were sacrificed and bronchoalveolar lavage (BAL) was performed for total cell count, differential, and permeability parameters. Inflammatory cytokine IL-6 levels were measured in BAL and plasma.


There was no difference between sham-operated or CLP-operated WT mice in total cell numbers in BAL. Sham operated Tie-2+/- mice had similar cell numbers, while ventilation in CLP-operated Tie-2+/- mice resulted in higher cell numbers (P = 0.06 versus WT), with an increase mainly in macrophages. IL-6 plasma levels were increased in septic Tie-2+/- mice subjected to mechanical ventilation compared with the WT mice, whereas IL-6 levels in BAL were not significantly different. Despite the higher total cell counts, permeability parameters measured in Tie-2+/- mice were lower than in WT mice (albumin, P = 0.08; total proteins, not significant; IgM, P = 0.05).


Pulmonary vascular permeability in mice with knockdown of endothelial Tie-2 receptor is preserved in ventilated septic mice. However, there was an increase in the number of inflammatory cells and systemic inflammation (IL-6) in these animals. These results further emphasize the importance of Tie-2 in regulating vascular permeability in the lungs.

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Mei, S., Haitsma, J., James, D. et al. The activity of the endothelial Tie-2 receptor modulates ventilation-induced lung injury in septic mice. Crit Care 11 (Suppl 4), P48 (2007).

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  • Total Cell Count
  • Peak Inspiratory Pressure
  • Cecum Ligation
  • Permeability Parameter
  • Inspire Oxygen Concentration