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

Toshifumi Tezuka,Masahiko Azuma,Yasuhiko Nishioka,Akiko Itai,Hirohisa Ogawa,Yoichi Yamaguchi,Hisatsugu Goto,Tomoyuki Fujikawa,Hisanori Uehara,Yoshinori Aono,Masaki Hanibuchi,Lynn M Schnapp

doi:10.1371/journal.pone.0121615

Toshifumi Tezuka, Masahiko Azuma + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0121615

Copy DOI

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.

Highlights

Bronchial asthma is characterized by allergic inflammation, airway hyperresponsiveness (AHR), and remodeling, including epithelial injury, subepithelial thickening/fibrosis, extracellular matrix (ECM) deposition, airway smooth muscle hyperplasia, goblet cell hypertrophy and hyperplasia, and angiogenesis [1].Recent studies suggest that the fibrinolytic system plays a key role in the development of airway remodeling
The level of total and active Plasminogen activator inhibitor (PAI)-1 was increased in Dermatophagoides pteronyssinus (Dp)/CMC mice compared with control/CMC mice in the lung homogenates (Fig. 2A and 2B)
The proportion of active PAI-1 as a percentage of the total PAI-1 in Dp/IMD mice was significantly lower than that in Dp/CMC mice (Fig. 2C). These results suggest that prolonged administration of IMD-4690 inhibits PAI-1 production as well as activation in the lungs of a mouse model of chronic asthma

Summary

Introduction

Recent studies suggest that the fibrinolytic system plays a key role in the development of airway remodeling. The key enzyme of fibrinolysis, is derived from plasminogen through the catalytic action of plasminogen activators (PAs), tissue-type PA (tPA) and urokinase-type PA (uPA) [2]. The tPA-mediated plasminogen activation plays a main role in the dissolution of fibrin in the circulation. UPA binds to a specific cellular receptor (uPAR), resulting in enhanced activation of cell-bound plasminogen [3]. Plasmin can degrade fibrin and activate the matrix metalloproteinase (MMP) system, which is involved in degrading ECM proteins (such as collagen) and neutralized by tissue inhibitors of metalloproteinase (TIMP) [4]. It was shown that enhancement of uPA/Plasmin activity reduces airway remodeling in a murine asthma model [5]

Methods

Results

Conclusion