TY - JOUR
T1 - Angiopoietin-1 treatment reduces inflammation but does not prevent ventilator-induced lung injury
AU - Hegeman, Maria A.
AU - Hennus, Marije P.
AU - van Meurs, Matijs
AU - Cobelens, Pieter M.
AU - Kavelaars, Annemieke
AU - Jansen, Nicolaas J.
AU - Schultz, Marcus J.
AU - van Vught, Adrianus J.
AU - Molema, Grietje
AU - Heijnen, Cobi J.
PY - 2010
Y1 - 2010
N2 - Background: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilatorinduced 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 mg 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.
AB - Background: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilatorinduced 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 mg 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.
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U2 - 10.1371/journal.pone.0015653
DO - 10.1371/journal.pone.0015653
M3 - Article
C2 - 21179479
AN - SCOPUS:78650763375
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 12
M1 - e15653
ER -