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KMID : 0620920080400030320
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Experimental & Molecular Medicine
2008 Volume.40 No. 3 p.320 ~ p.331
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Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury
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Kim So-Ri
Min Kyung-Hoon
Park Seoung-Ju
Lee Yong-Chul
Lee Ka-Young
Lee Kyung-Sun
Choe Yeong-Hun
Hong Sang-Hyun
Koh Gou-Young
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Abstract
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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-α, IL-1β, intercellular adhesion molecule-1, and vascular cell adhesion molecule- 1 in lungs, the levels of hypoxia-inducible factor- 1α (HIF-1α) and NF-κB 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-1α and NF-κB 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.
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KEYWORD
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angiopoietin-1, capillary permeability, COMP-Ang1 fusion protein, hydrogen peroxide, lung, pneumonia, reactive oxygen species, vascular endothelial growth factor A
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