Expression of plasminogen activator inhibitors type-1 and type-2 in the mouse lung after administration of crystalline silica

Lardot, C.; Heusterpreute, M; Mertens, Pascal; Philippe, Marianne; Lison, Dominique

doi:10.1183/09031936.98.11040912

Cited by 22 publications

(11 citation statements)

References 43 publications

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“…uPA mRNA levels displayed a rapid and marked upregulation after silica treatment, followed by a progressive decrease later on (28). Comparable changes have been found in the expression of plasminogen activator inhibitors type 1 and type 2 during the evolution of silicosis in mice lungs (29). These are important observations, because plasminogen activator appears to play a role in limiting fibrosis by disassembling the fibrin and procollagen scaffolds, and also by enhancing MMP activation.…”

Section: Discussionmentioning

confidence: 74%

Matrix Metalloproteinases 2, 9, and 13, and Tissue Inhibitors of Metalloproteinases 1 and 2 in Experimental Lung Silicosis

Pérez‐Ramos

Segura-Valdez

Cantón

et al. 1999

Am J Respir Crit Care Med

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Exposure to silica induces granulomatous lung inflammation evolving to fibrosis through yet unclear pathogenic mechanisms. We examined the expression of extracellular matrix remodeling molecules: collagenase 3, gelatinases A and B, and TIMP-1 and TIMP-2 in experimental lung silicosis. Rats were instilled with 50 mg of silica and sacrificed after 15 and 60 d. At 60 d a significant increase in lung collagen content was found (170.2 +/- 34.4 versus 88.2 +/- 20.8 microgram/mg in controls, p = 0.01). Gelatin zymography of bronchoalveolar lavage fluid (BALF) from 15 and 60 d revealed bands of progelatinase A and progelatinase B, and lung tissue zymograms showed in addition, the active gelatinase A form at 15 d. By in situ hybridization and immunohistochemistry, early silicotic granulomas exhibited intense staining for all matrix metalloproteinases (MMPs) and TIMPs assayed. Labeling was restricted inside granulomas and surrounding areas. Late silicotic granulomas at 60 d showed lower MMP expression than did early lesions, and in highly fibrotic nodules scarce signal was usually found. TIMP-1 and TIMP-2 showed a moderate reduction in 60-d silicotic nodules. These findings suggest that an imbalance in the expression of MMPs and TIMPs may be implicated in extracellular matrix remodeling and basement membrane disruption during experimental lung silicosis.

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Section: Discussionmentioning

confidence: 74%

Matrix Metalloproteinases 2, 9, and 13, and Tissue Inhibitors of Metalloproteinases 1 and 2 in Experimental Lung Silicosis

Pérez‐Ramos

Segura-Valdez

Cantón

et al. 1999

Am J Respir Crit Care Med

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“…PAI-3 regulates enzymes involved in fertilization rather than lung tissue fibrosis, whereas altered expression of both PAI-1 and PAI-2 is of potential relevance to the process of lung fibrosis (24,25). Although PAI-2 exhibits inhibitory activity toward tPA and uPA (26,27), the efficiency of PAI-2 is 20-to 100-fold less than what is observed for PAI-1 (28).…”

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

confidence: 86%

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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“…Silicosis is an occupational lung disease caused by inhalation of crystalline silica dust and features inflammation and scarring in the form of nodular lesions in the upper lobes of the lungs. Lardot et al (128) reported that a single intratracheal administration of a fibrosing dose of crystalline silica in mice increased PAI-1 activity and protein levels in macrophages and neutrophils from BALF, associated with an induction of PAI-1 and PAI-2 mRNA in lung tissue. Sustained upregulation of PAI-1 and PAI-2 mRNAs was still noted in lung tissue of these animals 1 month after silica treatment.…”

Section: Pai-1 and Lung Fibrosis: Animal Modelsmentioning

confidence: 99%

Oxidative Stress, Plasminogen Activator Inhibitor 1, and Lung Fibrosis

Liu

2008

Antioxidants & Redox Signaling

122

106

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Fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) in basement membranes and interstitial tissues, resulting from increased synthesis or decreased degradation of ECM or both. The plasminogen activator/plasmin system plays an important role in ECM degradation, whereas the plasminogen activator inhibitor 1 (PAI-1) is a physiologic inhibitor of plasminogen activators. PAI-1 expression is increased in the lung fibrotic diseases and in experimental fibrosis models. The deletion of the PAI-1 gene reduces, whereas the overexpression of PAI-1 enhances, the susceptibility of animals to lung fibrosis induced by different stimuli, indicating an important role of PAI-1 in the development of lung fibrosis. Many growth factors, including transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha), as well as other chemicals/agents, induce PAI-1 expression in cultured cells and in vivo. Reactive oxygen and nitrogen species (ROS/RNS) have been shown to mediate the induction of PAI-1 by many of these stimuli. This review summarizes some recent findings that help us to understand the role of PAI-1 in the development of lung fibrosis and ROS/RNS in the regulation of PAI-1 expression during fibrogenesis.

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Expression of plasminogen activator inhibitors type-1 and type-2 in the mouse lung after administration of crystalline silica

Cited by 22 publications

References 43 publications

Matrix Metalloproteinases 2, 9, and 13, and Tissue Inhibitors of Metalloproteinases 1 and 2 in Experimental Lung Silicosis

Matrix Metalloproteinases 2, 9, and 13, and Tissue Inhibitors of Metalloproteinases 1 and 2 in Experimental Lung Silicosis

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

Oxidative Stress, Plasminogen Activator Inhibitor 1, and Lung Fibrosis

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