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

So Ri Kim,Yeong Hun Choe,Gou Young Koh,Ka Young Lee,Sang Hyun Hong,Kyung Hoon Min,Kyung Sun Lee,Yong Chul Lee,Seoung Ju Park

doi: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-1beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and NF-kappaB 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-kB 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.

Highlights

Angiopoietin-1 (Ang1) has been identified as a secreted protein ligand of tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2) (Yancopoulos et al, 2000)
Western blot analysis revealed that levels of VEGF protein in lung tissues were increased significantly at 12 h after the last inhalation of H2O2 compared with the levels in the control mice (Figure 1A and B)
Consistent with the results obtained from the Western blot analysis, enzyme immunoassay revealed that levels of VEGF protein in Bronchoalveolar lavage (BAL) fluids were increased at 12 h after the last inhalation of H2O2 compared with the levels in the control mice (Figure 1C)

Summary

Introduction

Angiopoietin-1 (Ang1) has been identified as a secreted protein ligand of tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2) (Yancopoulos et al, 2000). Tie is a member of the receptor tyrosine kinase family and expressed predominantly on vascular endothelial cells, early hematopoietic cells, and their embryonic precursors (Jones et al, 2001). Ang can counteract VEGFinduced side effects (Kim et al, 2001) while having an additive effect on vessel formation (Chae et al, 2000). These observations have suggested that Ang has potential therapeutic applications in inducing angiogenesis, enhancing endothelial cell survival, and preventing vascular leakage. We have developed a soluble, stable, and potent Ang variant, COMP-Ang (Cho et al, 2004). COMPAng is an effective alternative to native Ang for therapeutic application in vivo

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Results

Conclusion