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Abstract

Mice deleted for the plasminogen activator inhibitor-1 (PAI-1) gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. We hypothesized that PAI-1 deficiency reduces fibrosis by promoting plasminogen activation and accelerating the clearance of fibrin matrices that accumulate within the damaged lung. In support of this hypothesis, we found that the lungs of PAI-1–/– mice accumulated less fibrin after injury than wild-type mice, due in part to enhanced fibrinolytic activity. To further substantiate the importance of fibrin removal as the mechanism by which PAI-1 deficiency limited bleomycin-induced fibrosis, bleomycin was administered to mice deficient in the gene for the Aα-chain of fibrinogen (fib). Contrary to our expectation, fib–/– mice developed pulmonary fibrosis to a degree similar to fib+/– littermate controls, which have a plasma fibrinogen level that is 70% of that of wild-type mice. Although elimination of fibrin from the lung was not in itself protective, the beneficial effect of PAI-1 deficiency was still associated with proteolytic activity of the plasminogen activation system. In particular, inhibition of plasmin activation and/or activity by tranexamic acid reversed both the accelerated fibrin clearance and the protective effect of PAI-1 deficiency. We conclude that protection from fibrosis by PAI-1 deficiency is dependent upon increased proteolytic activity of the plasminogen activation system; however, complete removal of fibrin is not sufficient to protect the lung.

Authors

Noboru Hattori ... Richard H. Simon, Angela F. Drew

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Total citations by year

Year: 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 Total
Citations: 5 12 12 5 5 14 4 10 11 8 11 3 2 1 103
Citation information

Citations to this article in year 2005 (11)

Title and authors Publication Year
Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator
A Giorgio-Miller, S Bottoms, G Laurent, P Carmeliet, S Herrick
The American Journal of Pathology 2005
Modulation of Prosurvival Signaling in Fibroblasts by a Protein Kinase Inhibitor Protects against Fibrotic Tissue Injury
R Vittal, JC Horowitz, BB Moore, H Zhang, FJ Martinez, GB Toews, TJ Standiford, VJ Thannickal
The American Journal of Pathology 2005
Multifunctionality of PAI-1 in fibrogenesis: Evidence from obstructive nephropathy in PAI-1-overexpressing mice1
S Matsuo, JM Lopez-Guisa, X Cai, DM Okamura, CE Alpers, RE Bumgarner, MA Peters, G Zhang, AA Eddy
Kidney International 2005
Pediatric lung disease: From proteinases to pulmonary fibrosis
F Chua, PD Sly, GJ Laurent
Pediatric Pulmonology 2005
Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-gamma
JH Kim, HY Kim, S Kim, JH Chung, WS Park, DH Chung
The American Journal of Pathology 2005
Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis
DC Howell, RH Johns, JA Lasky, B Shan, CJ Scotton, GJ Laurent, RC Chambers
The American Journal of Pathology 2005
An unexpected role of plasminogen activator inhibitor-type 1 (PAI-1) in renal fibrosis
Y Huang, N Noble
Kidney International 2005
Natural Killer T (NKT) Cells Attenuate Bleomycin-Induced Pulmonary Fibrosis by Producing Interferon-γ
JH Kim, HY Kim, S Kim, JH Chung, WS Park, DH Chung
The American Journal of Pathology 2005
Multifunctionality of PAI-1 in fibrogenesis: Evidence from obstructive nephropathy in PAI-1-overexpressing mice1
S Matsuo, JM Lopez-Guisa, X Cai, DM Okamura, CE Alpers, RE Bumgarner, MA Peters, G Zhang, AA Eddy
Kidney International 2005
An unexpected role of plasminogen activator inhibitor-type 1 (PAI-1) in renal fibrosis
Y Huang, N Noble
Kidney International 2005
Pulmonary Fibrosis: Searching for Model Answers
F Chua, J Gauldie, GJ Laurent
American journal of respiratory cell and molecular biology 2005

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