Plasminogen activation by airway smooth muscle is regulated by type I collagen.
Plasmin, the activated protease product of plasminogen, is involved in collagen remodeling, and is strongly implicated in asthma pathophysiology by recent genome-wide association studies. This study examines plasminogen "activation" by airway smooth muscle cells, and its regulation in a fibrotic environment created by culture on type I collagen and incubation with transforming growth factor (TGF)-β. Urokinase plasminogen activator (uPA) activity was detected in the supernatants of human airway smooth muscle cell cultures maintained in serum-free conditions. Incubation with plasminogen (1.5-50.0 μg/ml, 24 h) increased plasmin activity in a concentration-dependent manner (P < 0.001). uPA activity was higher in cultures maintained on fibrillar type I collagen substrata than in those on plastic, as was plasmin activity after incubation with plasminogen (20 μg/ml). Pretreatment with TGF-β (100 pM) for 18 hours inhibited plasminogen activation by airway smooth muscle cells maintained on plastic, but not on collagen. TGF-β stimulated an increase in the level of uPA mRNA in airway smooth muscle cells grown on collagen, but not on plastic. Reducing the levels of β1-integrin collagen receptor, using interference RNA, attenuated plasmin formation by airway smooth muscle cells grown on collagen, and restored the inhibitory effect of TGF-β. This study shows that airway smooth muscle activation of plasminogen by uPA is accelerated in a collagen-rich environment in which the inhibitory effect of TGF-β is attenuated in association with greater uPA expression induced via β1-integrin signaling. These findings suggest that the plasminogen-activation system involving uPA has the potential to contribute to airway wall remodeling in asthma.
Schuliga
Michael
M
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia. schuliga@unimelb.edu.au
Harris
Trudi
T
Stewart
Alastair G
AG
D001249:Asthma / Q000378:metabolism; D002364:Caseins / Q000737:chemistry; D024042:Collagen Type I / Q000737:chemistry / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008954:Models, Biological; D009130:Muscle, Smooth / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D002364:Caseins; D024042:Collagen Type I; D019012:Integrin beta1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator