title: IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.
abstract: Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tezuka
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.affiliation: Institute of Medicinal Molecular Design Inc., Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Institute of Medicinal Molecular Design Inc., Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujikawa
authors.affiliation: Institute of Medicinal Molecular Design Inc., Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001980:Bronchi / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism
chemical_list: C000604870:2-((3-(4-tert-butylphenoxy)-4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)acetic acid; D000085:Acetates; D039741:Antigens, Dermatophagoides; D001713:Biphenyl Compounds; D016207:Cytokines; D017395:Plasminogen Activator Inhibitor 1; D007073:Immunoglobulin E; D010959:Tissue Plasminogen Activator