title: Angiopoietin-1 treatment reduces inflammation but does not prevent ventilator-induced lung injury.
abstract: BACKGROUND
  Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation.
  
  
  METHODS
  Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH2O ('low' tidal volume ∼7.5 ml/kg; LVT) or 18 cmH2O ('high' tidal volume ∼15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 µg per animal). Non-ventilated mice served as controls.
  
  
  RESULTS
  HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1β caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression.
  
  
  CONCLUSIONS
  Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilation.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, Department of Pediatric Intensive Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Hegeman
authors.forename: Marije P
authors.initials: MP
authors.lastname: Hennus
authors.forename: Matijs
authors.initials: M
authors.lastname: van Meurs
authors.forename: Pieter M
authors.initials: PM
authors.lastname: Cobelens
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Nicolaas J
authors.initials: NJ
authors.lastname: Jansen
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: Adrianus J
authors.initials: AJ
authors.lastname: van Vught
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D042683:Angiopoietin-1 / Q000627:therapeutic use*; D000818:Animals; D001784:Blood Gas Analysis; D006098:Granulocytes / Q000166:cytology; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D015603:Keratinocytes / Q000166:cytology; D055370:Lung Injury / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000378:metabolism*; D055397:Ventilator-Induced Lung Injury / Q000517:prevention & control*
chemical_list: D042683:Angiopoietin-1; D042787:Receptor, TIE-2