Blockade of airway inflammation and hyper-responsiveness by an angiopoietin-1 variant, COMP-Ang1

Kyung Sun Lee,Gou Young Koh,Kyung Hoon Min,Chung-Hyun Cho,Ka Young Lee,Seoung Ju Park,Ho Sung Park,So Ri Kim,Yong Chul Lee,Hee Sun Park

doi:10.1038/emm.2007.80

Kyung Sun Lee, Gou Young Koh + Show 8 more

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https://doi.org/10.1038/emm.2007.80

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Abstract

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage. Recently, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 receptor in lung endothelial cells. We have used a mouse model for allergic airway disease to determine effects of COMP-Ang1 on allergen-induced bronchial inflammation and airway hyper-responsiveness. These mice develop the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased levels of Th2 cell cytokines (IL-4, IL-5, and IL-13), adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), and chemokines (eotaxin and RANTES), and increased vascular permeability. Intravenous administration of COMP-Ang1 reduced bronchial inflammation and airway hyper-responsiveness. In addition, the increased plasma extravasation in allergic airway disease was significantly reduced by the administration of COMP-Ang1. These results suggest that COMP-Ang1 attenuates airway inflammation and hyper-responsiveness, prevents vascular leakage, and may be used as a therapeutic agent in allergic airway disease.

Highlights

Bronchial asthma is a chronic inflammatory disease of the airways that is characterized by airway remodeling, which is usually accompanied by increased vascular permeability, resulting in plasma exudation (Bousquet et al, 2000)
Bronchial asthma is characterized by inflammation of the airways which is usually accompanied by increased vascular permeability, resulting in plasma exudation
Our present study with the OVA-induced murine model of allergic airway disease revealed that COMPAng1, which is more potent than native Ang1 in phosphorylating the Tie2 receptor in lung endothelial cells, reduces antigen-induced airway infiltration of inflammatory cells, increased secretion of Th2 cytokines in lungs, airway hyper-responsiveness to methacholine, and increased vascular permeability

Summary

Introduction

Bronchial asthma is a chronic inflammatory disease of the airways that is characterized by airway remodeling, which is usually accompanied by increased vascular permeability, resulting in plasma exudation (Bousquet et al, 2000). Increased vascular permeability causes leakage of intravascular components, including plasma extravasation. Exudation of plasma proteins into the airways contributes to the airway obstruction and hyper- responsiveness (Van de Graaf et al, 1991; Lee et al, 2002). Angiopoietin-1 (Ang1) has been identified as a secreted protein ligand of tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) (Yancopoulos et al, 2000). Tie is a mem ber of the receptor tyrosine kinase family and is expressed predominantly on vascular endothelial cells, early hematopoietic cells, and their embryonic precursors (Takakura et al, 2000; Jones et al, 2001).

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