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Critical Care

Volume 11 Supplement 4

Sepsis 2007

Open Access

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

  • Shirley Mei1, 2,
  • Jack Haitsma3,
  • Daniel James3,
  • Colleen Parker2,
  • Arthur Slutsky3 and
  • Duncan Stewart1, 2
Critical Care200711(Suppl 4):P48

Published: 26 September 2007


Total Cell CountPeak Inspiratory PressureCecum LigationPermeability ParameterInspire Oxygen Concentration


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.

Authors’ Affiliations

Institute of Medical Science, University of Toronto, Toronto, Canada
Terrence Donnelly Heart Centre, St Michael's Hospital, Toronto, Canada
Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada


© BioMed Central Ltd 2007