Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Abstract

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model. Am J Physiol Lung Cell Mol Physiol 296: L337-L346, 2009. First published December 19, 2008 doi:10.1152/ajplung.90434.2008.-The airway remodeling that occurs in asthma is characterized by an excess of extracellular matrix deposition in the submucosa, hyperplasia/hypertrophy of smooth muscle, goblet cell metaplasia, and accumulation of fibroblasts/myofibroblasts. The urokinase-type plasminogen activator (uPA)/plasmin system participates in pericellular proteolysis and is capable of directly degrading matrix components, activating latent proteinases, and activating growth factors. In a mouse ovalbumin (OVA) asthma model, we increased plasminogen activator activity in the lung by administering exogenous uPA or by using mice genetically deficient in the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) to assess the role of this system in asthma pathogenesis. After intraperitoneal OVA sensitization, mice inhaled OVA plus uPA (500 IU/ mouse) or saline by ultrasonic nebulization for 3 wk. When studied 24 h after the final exposure, the groups with upregulated plasmin activity had significantly reduced subepithelial fibrosis within the airway walls and had decreased airway hyperresponsiveness (AHR) to methacholine. Morphometric analysis showed that subepithelial wall thickening of the bronchi (subepithelial area ratio) was also reduced, as were collagen and ␣-smooth muscle actin. Upregulation of plasmin activity also increased the level of hepatocyte growth factor activity in bronchoalveolar lavage fluid, whereas the release of transforming growth factor-␤ was decreased. The administration of uPA 1 wk after the last OVA inhalation also significantly reduced lung hydroxyproline content and AHR. These results show that enhancing uPA/ plasmin activity lessens the airway remodeling in a murine asthma model.

Concentrations of plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) in induced sputum of asthma patients after allergen challenge.

“…This study supports previous observations linking the plasmin system with pathogenesis of allergic asthma [8][9][10][11][12][13][14][15][16]. In the present study we demonstrate that, in the airways of allergic asthma patients, allergen exposure leads to up-regulation of both components of the plasmin system: PAI-1 and uPA.…”

“…In an animal asthma model either suppression of PAI-1 expression by knockout of the PAI-1 gene or delivery of exogenous uPA leads to decreased airway remodeling and decreased airway hyperresponsiveness [7][8][9]. In humans, genetic variants of uPA and PAI-1 genes are associated with increased risk of allergic asthma [10][11][12][13][14][15].…”

Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells

“…The induction of PAI-1 expression is related to collagen deposition in murine asthma model [50]. In view of the fact that Smad3 siRNA transfection did not induce the activities of NF-κB or PAI-1 in Smad3 downstream signal cascades in BMMCs, we suggest that cigarette smoke may induce collagen deposition by mast cell activation through TGF-β/Smad signaling pathways.…”

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

“…Enhancing uPA/plasmin activity lessens the airway remodeling in a murine asthma model. 32 This remains the case, even though there is compelling evidence of uPA involvement in tissue remodeling, and uPA has attracted attention as an emerging therapeutic target in cancer. 33 Genetic studies have also shown an essential role of uPA in tissue healing or regeneration.…”