Exp Mol Med.  2008 Jun;40(3):320-331. 10.3858/emm.2008.40.3.320.

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

• Kim SR
• Lee KS
• Park SJ
• Min KH
• Lee KY
• Choe YH
• Hong SH
• Koh GY
• Lee YC

• KMID: 756334
• DOI: http://doi.org/10.3858/emm.2008.40.3.320

Abstract

Reactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP- Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-alpha, IL-1 beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1 alpha) and NF-kappa B in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H2O2. We have also found that the activation of HIF-1a and NF-kappa B and the increase of phosphoinositide 3-kinase activity in lung tissues after H2O2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.

Keyword

angiopoietin-1; capillary permeability; COMP-Ang1 fusion protein; hydrogen peroxide; lung; pneumonia; reactive oxygen species; vascular endothelial growth factor A

MeSH Terms

Acute Lung Injury/chemically induced/complications/*drug therapy/metabolism
Administration, Inhalation
Airway Resistance/drug effects
Animals
Bronchial Hyperreactivity/drug therapy/etiology
Bronchoalveolar Lavage Fluid
Capillary Permeability/*drug effects
Cytokines/antagonists & inhibitors
Female
Hydrogen Peroxide/adverse effects
Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
Intercellular Adhesion Molecule-1/metabolism
Mice
Mice, Inbred BALB C
NF-kappa B/antagonists & inhibitors
Pneumonia/*drug therapy/etiology
Recombinant Fusion Proteins/*administration & dosage
Vascular Cell Adhesion Molecule-1/metabolism