PAI-1 promotes extracellular matrix deposition in the airways of a murine asthma model.
Dysregulation of matrix metalloproteinases (MMPs) and ineffective fibrinolysis are associated with the deposition of extracellular matrix (ECM). We hypothesized that elevated plasminogen activator inhibitor (PAI)-1 promotes ECM deposition in the asthmatic airway by inhibiting MMP-9 activity and fibrinolysis. Degree of airway inflammation was similar in PAI-1(-/-) and wild type (WT) mice after ovalbumin (OVA) challenge. PAI-1 production, deposition of collagen and fibrin, and MMP-9 activity in the lung tissue or airways were greater after OVA challenge compared with saline challenge. However, in PAI-1(-/-) mice, collagen deposition was 2-fold less, fibrin deposition was 4-fold less, and MMP-9 activity was 3-fold higher. This is the first direct evidence that the plasmin system regulates ECM deposition in the airways of a murine asthma model, independently of the effect of PAI-1 on inflammatory cells. The results suggest that the PAI-1-dependent inhibition of MMP-9 activity and fibrinolysis is a major mechanism by which ECM deposition occurs.
Oh
Chad K
CK
Division of Allergy and Immunology, Department of Pediatrics, UCLA School of Medicine, Harbor-UCLA Medical Center, School of Medicine, University of California, Bldg. N25, 1000 W. Carson St., Los Angeles, Torrance, CA 90509, USA. coh@rei.edu
Ariue
Barbara
B
Alban
Rodrigo F
RF
Shaw
Bryan
B
Cho
Seong H
SH
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003094:Collagen / Q000032:analysis; D005109:Extracellular Matrix / Q000378:metabolism*; D005337:Fibrin / Q000096:biosynthesis; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D007073:Immunoglobulin E; D005337:Fibrin; D010047:Ovalbumin; D003094:Collagen; D020780:Matrix Metalloproteinase 9