Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene.

Eitzman, Daniel T.; McCoy, Ronald D.; Zheng, Xianxian; Fay, William P.; Shen, Tingliang; Ginsburg, David; Simon, Richard H.

doi:10.1172/jci118396

Cited by 542 publications

(425 citation statements)

References 35 publications

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“…PAI-1 is the major physiological inhibitor of plasmin generation (85). High levels of PAI-1 are believed to favor the development of fibrosis in various types of inflammatory conditions (86) and glomerular diseases, including diabetic nephropathy (6,87), presumably because plasmin degrades ECM and activates other ECM-degrading metalloproteinases (85,86). In the current experiments, increases in UDP-HexNAc levels and PAI-1 gene expression were achieved by glucosamine.…”

Section: Discussionmentioning

confidence: 61%

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

2000

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Increased flux through the hexosamine biosynthetic pathway is associated with altered gene expression. To investigate the underlying mechanisms, we treated glomerular mesangial cells with glucosamine and studied the regulation of the plasminogen activator inhibitor (PAI)-1 gene. Incubating mesangial cells with 2 mmol/l glucosamine for 4 days resulted in a 3.1 ± 0.4-fold increase in PAI-1 mRNA levels (P < 0.01) and a 33 ± 9-fold increase in the activity of a transiently transfected PAI-1 promoter-luciferase reporter gene (P < 0.01). Cotransfection of an expression vector for a dominant-negative type II TGF-␤ receptor with the PAI-1 promoter-reporter gene did not interfere with this effect of glucosamine. However, mutation of 2 putative Sp1 sites in the PAI-1 promoter, at -76 to -71 and -44 to -39, markedly reduced induction of PAI-1 luciferase activity by glucosamine, from 8.9 ± 1.9-fold to 1.7 ± 0.5-fold (P < 0.01). An electrophoretic mobility shift assay demonstrated that glucosamine increased Sp1 DNA binding by 31 ± 11% (P < 0.05), implying that the effects of glucosamine were explained, in part, by changes in Sp1 DNA binding. High glucose (20 mmol/l) also activated the transiently transfected PAI-1 promoter (2.5 ± 0.4-fold). This effect was diminished by mutation of both the PAI-1 promoter Sp1 sites (1.2 ± 0.3-fold, P < 0.05). In addition, 6-diazo-5-oxo-L-norleucine, a glutamine:fructose-6-phosphateamidotransferase inhibitor, blocked the induction by high glucose (4.7 ± 0.8-to 0.9 ± 0.1-fold, P < 0.01). These results indicate that stimulation of the PAI-1 promoter by both high glucose and glucosamine involves Sp1 and that the hexosamine pathway may be involved in the regulation of gene expression by high glucose in glomerular mesangial cells. Diabetes 49:863-871, 2000

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Section: Discussionmentioning

confidence: 61%

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

2000

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“…An association between reduced fibrinolysis and the development of fibrosis has been highlighted in other pathological experimental model systems in studies similar to ours using mice with overexpression or underexpression of various components of the fibrinolytic system. 22,23,34,35 Eitzman and colleagues 22 found that overexpression of PAI-1, resulted in enhanced deposition of collagen in the lungs of bleomycin-treated mice, whereas PAI-1-deficient mice produced levels of collagen comparable to wildtype controls. Of particular interest, a study by Swaisgood and colleagues 23 also using PA-deficient mice, showed that bleomycin-instillation resulted in approximately a twofold increase in the amount of collagen in the lungs of tPA-deficient mice compared with uPA-deficient and wild-type mice directly correlating with findings in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…After bleomycin-induced lung injury, mice deficient in plasminogen, uPA, or tPA, or those that overexpress PAI-1, show extensive fibrin deposition, collagen accumulation, and accelerated pulmonary fibrosis when compared with control mice. 22,23 These studies concluded that reduced fibrinolysis results in fibrin accumulation at the site of injury and subsequent fibrosis ensues. However, despite evidence in other systems, an association between the persistence of fibrin and increased collagen accumulation in the skin has not been shown.…”

mentioning

confidence: 99%

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Giorgio-Miller

Bottoms

Laurent

et al. 2005

The American Journal of Pathology

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The deposition of fibrin is an integral part of the tissue repair process, but its persistence is also associated with a number of fibrotic conditions. This study addressed the hypothesis that reduced fibrinolysis and fibrin persistence are associated with an enhanced accumulation of collagen and the development of skin fibrosis. Decreased fibrinolysis was confirmed in fibrin gel cultures that contained human dermal fibroblasts plus the specific plasmin inhibitor ␣ 2 -antiplasmin or dermal fibroblasts isolated from plasminogen activator (PA)-deficient mice. Collagen accumulation was significantly increased in the presence of inhibitor and in tPA-deficient, but not uPAdeficient, fibroblasts compared with controls. These findings were also confirmed using a skin fibrosis model in which multiple injections of fibrin were given subcutaneously to PA-deficient mice. Injection sites from tPA-deficient mice displayed significantly increased collagen levels compared with uPA-deficient mice and wild-type controls. Up-regulation of fibroblast procollagen gene expression and reduced activation of pro-MMP-1 appeared to mediate the increase in collagen by human dermal fibroblasts in the presence of ␣2-antiplasmin. These findings suggest that persistent fibrin is associated with enhanced collagen accumulation that may result in the development of fibrotic skin disorders in which reduced fibrinolysis is a feature.

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“…PAI-1-deficient mice are resistant to pulmonary fibrosis after lung injury, presumably due to accelerated fibrinolysis (35). PAI-1-overexpressing mice suffered a severe lung injury and deposition of ECM after bleomycin challenge (35) or hyperoxia (36), whereas PAI-1-deficient mice were protected against such fibrotic reaction.…”

Section: Ast Cells Are Multifunctional Effector Cells That Partic-mentioning

confidence: 99%

Production of Plasminogen Activator Inhibitor-1 by Human Mast Cells and Its Possible Role in Asthma

Cho¹,

Tam²,

Demissie-Sanders³

et al. 2000

The Journal of Immunology

118

114

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The plasminogen activator inhibitor type 1 (PAI-1) has an essential role in tissue remodeling. The PAI-1 gene was induced by a combination of phorbol ester and calcium ionophore at the highest level among the inducible human mast cell genes that we have analyzed on a DNA microarray. PAI-1 was secreted by both a human mast cell line (HMC)-1 and primary cultured human mast cells upon stimulation, whereas PAI-1 was undetectable in either group of unstimulated cells. The secretion of PAI-1 was due to de novo synthesis of PAI-1 rather than secretion of preformed PAI-1. The functional significance of PAI-1 secretion was demonstrated by complete inhibition of tissue-type plasminogen activator activity with supernatants of stimulated HMC-1 cells. Furthermore, we were able to regulate PAI-1 gene expression in HMC-1 cells by known therapeutic agents. High-dose (1 μM) dexamethasone induced PAI-1 mRNA expression. Cyclosporin down-regulated the expression of the PAI-1 gene. Cycloheximide abrogated PAI-1 mRNA expression, suggesting that transcription of the PAI-1 gene requires de novo synthesis of early gene products, including transcription factors. Finally, we demonstrated PAI-1 in lung mast cells from a patient with asthmatic attack by double-immunofluorescence study. This is the first report demonstrating that activated human mast cells release a striking amount of functionally active PAI-1. These results suggest that PAI-1 could play an important role in airway remodeling of asthma, and inhibition of PAI-1 activity could represent a novel therapeutic approach in the management of airway remodeling.

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Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene.

Cited by 542 publications

References 35 publications

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Production of Plasminogen Activator Inhibitor-1 by Human Mast Cells and Its Possible Role in Asthma

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