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

Rui Ming Liu, Stephanie Eldridge, Nobuo Watanabe, Jessy Deshane, Hui Chien Kuo, Chunsun Jiang, Yong Wang, Gang Liu, Lisa Schwiebert, Toshio Miyata, Victor J. Thannickal

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 tissuetype 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 OVAinduced 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.

Original languageEnglish
Pages (from-to)L328-L336
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume310
Issue number4
DOIs
Publication statusPublished - 2016 Feb 15

Keywords

  • Animal model
  • Plasminogen activator inhibitor 1
  • Plasminogen activator inhibitor 1 inhibitor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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