title: Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma.
abstract: Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms, there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators, has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small-molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyperresponsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor TM5275 may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; rliu@uab.edu.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Eldridge
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Tohoku, Japan;
authors.forename: Nobuo
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Jessy
authors.initials: J
authors.lastname: Deshane
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Hui-Chien
authors.initials: HC
authors.lastname: Kuo
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Chunsun
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schwiebert
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Tohoku, Japan;
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D010047:Ovalbumin / Q000008:administration & dosage / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D015849:Plasminogen Inactivators / Q000008:administration & dosage / Q000627:therapeutic use*; D062366:para-Aminobenzoates / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D016207:Cytokines; D010879:Piperazines; D015849:Plasminogen Inactivators; D062366:para-Aminobenzoates; D010047:Ovalbumin
keywords: animal model; plasminogen activator inhibitor 1; plasminogen activator inhibitor 1 inhibitor