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 tissue type and urokinase type plasminogen activators (tPA and uPA, respectively), 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 hyper-responsiveness in an OVA-induced 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.
Am J Physiol Lung Cell Mol Physiol. 2015 Dec 23;:ajplung.00217.2015
Authors: Liu RM, Eldridge S, Watanabe N, Deshane JS, Kuo HC, Jiang C, Wang Y, Liu G, Schwiebert LM, Miyata T, Thannickal VJ
