title: Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury.
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.
authors.affiliation: Department of Internal Medicine and Airway Remodeling Laboratory, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.forename: Kyung Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Seoung Ju
authors.initials: SJ
authors.lastname: Park
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
authors.forename: Ka Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Yeong Hun
authors.initials: YH
authors.lastname: Choe
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000209:etiology; D001992:Bronchoalveolar Lavage Fluid; D002199:Capillary Permeability / Q000187:drug effects*; D016207:Cytokines / Q000037:antagonists & inhibitors; D005260:Female; D006861:Hydrogen Peroxide / Q000009:adverse effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011014:Pneumonia / Q000188:drug therapy* / Q000209:etiology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C515576:COMP-Ang1 fusion protein; D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D006861:Hydrogen Peroxide