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

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.

Plasminogen activator inhibitor-1 does not contribute to the pulmonary pathology induced by acute exposure to ozone

“…; Tezuka et al. ). Therefore, increases in pulmonary expression of PAI‐1 subsequent to lung injury appear to be a nonspecific response, yet it is uncertain whether this phenomenon is beneficial or unfavorable.…”

“…; Tezuka et al. ; Liu et al. ), which are all pathological features induced by inhalation of O 3 (Bhalla et al.…”

Effects of epinephrine on angiogenesis-related gene expressions in cultured rat cardiomyocytes

“…Lower level of PAI-1 would presumably lead to less suppression of fibrinolysis and conversely a more rapid degradation of fibrin. A recent study reported that inhibition of PAI-1 may decrease angiogenesis [ 23 ] . Thus, decreased expression of SERPINE1(−2.42 times) seems create a disadvantageous environment for angiogenesis in myocardium.…”

Where does current and future pediatric asthma treatment stand? Remodeling and inflammation: Bird's eye view

“…PAI‐1 which leads to excess extracellular matrix formation, is found to be higher in bronchoalveolar lavage and induced sputum of patients with asthma, which was interpreted in favor of the potential action of this protease inhibitor in remodeling pathogenesis. Studies have shown that inhibition of PAI‐1 in mouse model of asthma, attenuates inflammatory cell infiltration of the airways and decreases in collagen deposition, goblet cell hyperplasia, sub‐epithelial smooth muscle thickness, and vascular density which are all components of airway remodeling …”