Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model.
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 alpha-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-beta 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.
Kuramoto
Emi
E
Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
Nishiuma
Teruaki
T
Kobayashi
Kazuyuki
K
Yamamoto
Masatsugu
M
Kono
Yuko
Y
Funada
Yasuhiro
Y
Kotani
Yoshikazu
Y
Sisson
Thomas H
TH
Simon
Richard H
RH
Nishimura
Yoshihiro
Y
D000280:Administration, Inhalation; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005341:Fibrinolysin / Q000502:physiology; D005342:Fibrinolysis; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D058258:Serpin E2; D015843:Serpins / Q000172:deficiency / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000502:physiology
D017931:DNA Primers; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D010047:Ovalbumin; D003094:Collagen; D019859:Proto-Oncogene Proteins c-met; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D006909:Hydroxyproline