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.