Angiopoietin-1 treatment reduces inflammation but does not prevent ventilator-induced lung injury

• Published in: PloS one Vol. 5; no. 12; p. e15653
• Main Authors: Hegeman, Maria A, Hennus, Marije P, van Meurs, Matijs, Cobelens, Pieter M, Kavelaars, Annemieke, Jansen, Nicolaas J, Schultz, Marcus J, van Vught, Adrianus J, Molema, Grietje, Heijnen, Cobi J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.12.2010; Public Library of Science (PLoS)
• Subjects: AKT protein; Angiopoietin; Angiopoietin-1 - therapeutic use; Animals; Asthma; Biology; Blood Gas Analysis; Disease; Edema; Endothelium; Gas exchange; Gene expression; Granulocytes - cytology; Hemodynamics; Humans; IL-1β; Infiltration; Inflammation; Inflammation - drug therapy; Injury prevention; Integrity; Intensive care; Interleukin; Interleukins; Keratinocytes - cytology; Kinases; Laboratories; Leakage; Leukocytes (granulocytic); Lung diseases; Lung Injury - metabolism; Lungs; Macrophage inflammatory protein; Macrophages; Male; Mechanical ventilation; Medicine; Mice; Mice, Inbred C57BL; Monocytes; mRNA; Neutrophils; Pediatrics; Permeability; Phosphorylation; Proteins; Receptor, TIE-2 - metabolism; Respiration; Respiratory distress syndrome; Respiratory system agents; Rodents; Signaling; Transcription factors; Tumor necrosis factor-TNF; Vascular endothelial growth factor; Ventilation; Ventilator-Induced Lung Injury - prevention & control; Ventilators; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015653

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. 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. 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. 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.