A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma

Sun H. Lee, Mesut Eren, Douglas E. Vaughan, Robert P. Schleimer, Seong H. Cho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice wereimmunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Startingon Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree ofgoblet cellhyperplasia andcollagen depositionin theairways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma.

Original languageEnglish (US)
Pages (from-to)842-846
Number of pages5
JournalAmerican journal of respiratory cell and molecular biology
Volume46
Issue number6
DOIs
StatePublished - Jun 1 2012

Keywords

  • Airway remodeling
  • Asthma
  • Collagen deposition
  • Plasminogen activator inhibitor-1
  • Tiplaxtinin

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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