Format

Send to

Choose Destination
Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L328-36. doi: 10.1152/ajplung.00217.2015. Epub 2015 Dec 23.

Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma.

Author information

1
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; rliu@uab.edu.
2
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
3
United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Tohoku, Japan;
4
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; and.
5
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.

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.

KEYWORDS:

animal model; plasminogen activator inhibitor 1; plasminogen activator inhibitor 1 inhibitor

PMID:
26702150
PMCID:
PMC4754904
DOI:
10.1152/ajplung.00217.2015
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center