Glutathione restores collagen degradation in TGF-β-treated fibroblasts by blocking plasminogen activator inhibitor-1 expression and activating plasminogen

Vayalil, Praveen K.; Olman, Mitchell A.; Murphy-Ullrich, Joanne E.; Postlethwait, Edward M.; Liu, Rui Ming

doi:10.1152/ajplung.00150.2005

Cited by 32 publications

(49 citation statements)

References 76 publications

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“…u-PAR can regulate plasminogen-induced apoptosis of fibroblasts through enhancement of cell surface plasminogen activation upon ligation with u-PA, an effect blunted by TGF␤-mediated induction of PAI-1 (26). We have shown that repletion of glutathione, a potent antioxidant, in TGF␤-treated fibroblasts restores the TGF␤-induced collagen degradation defect (61) and, furthermore, that the effect of glutathione on overall collagen degradation in TGF␤-treated fibroblasts is a consequence of regulation of plasminogen activation (61).…”

Section: Discussionmentioning

confidence: 80%

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Zhu

Gladson

White

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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MA. Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins. Am J Physiol Lung Cell Mol Physiol 297: L97-L108, 2009. First published May 1, 2009 doi:10.1152/ajplung.90283.2008.-Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize ␣ v␤5 to attach to vitronectin, predominantly ␣5␤1 (and ␣v␤3) to attach to fibronectin, and ␣ 1␤1, ␣2␤1, and ␣3␤1 to attach to collagen. Blocking studies with ␣-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrinmediated attachment to purified provisional matrix proteins, to antiintegrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple ␣-integrins but with a preference for ␣ 3. Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung. pulmonary; fibrosis; plasmin STUDIES IN VITRO AND IN TRANSGENIC animals have demonstrated that the fibrinolytic system has protean effects on numerous disease processes including acute and chronic inflammatory disorders, cancer invasion and metastasis, angiogenesis, and fibroproliferative disorders of the vasculature, lung, kidney, and eye (3,4,11,16,22,23,27,29,37,55). These disorders have the common feature of a complex, yet coordinated movement of cells and the biochemical and structural remodeling of the extracellular matrix. The molecular interactions and cell biological processes that mediate the effects of the fibrinolytic system on cell-matrix interactions are active areas of investigation.Protease-protease inhibitor mechanisms of the urokinase/ plasmin system that relate to intravascular or alveolar fibrin turnover are deranged in pulmonary fibrosis but are clearly only a part of the relevant biology (38). The recep...

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Section: Discussionmentioning

confidence: 80%

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Zhu

Gladson

White

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It is known that GSH plays a prominent role in immune responses (17,23,29,38), extracellular matrix remodeling (50,56), and in inflammatory responses (43). Chronic bronchopulmonary infection is a hallmark feature in CF patients.…”

Section: Discussionmentioning

confidence: 99%

A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration

Kariya¹,

Leitner²,

Min³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the only known apical glutathione (GSH) transporter in the lung. The purpose of these studies was to determine whether oral GSH or glutathione disulfide (GSSG) treatment could increase lung epithelial lining fluid (ELF) GSH levels and whether CFTR plays a role in this process. The pharmacokinetic profile of an oral bolus dose of GSH (300 mg/kg) was determined in mice. Plasma, ELF, bronchoalveolar lavage (BAL) cells, and lung tissue were analyzed for GSH content. There was a rapid elevation in the GSH levels that peaked at 30 min in the plasma and 60 min in the lung, ELF, and BAL cells after oral GSH dosing. Oral GSH treatment produced a selective increase in the reduced and active form of GSH in all lung compartments examined. Oral GSSG treatment (300 mg/kg) resulted in a smaller increase of GSH levels. To evaluate the role of CFTR in this process, Cftr knockout (KO) mice and gut-corrected Cftr KO-transgenic (Tg) mice were given an oral bolus dose of GSH (300 mg/kg) and compared with wild-type mice for changes in GSH levels in plasma, lung, ELF, and BAL cells. There was a twofold increase in plasma, a twofold increase in lung, a fivefold increase in ELF, and a threefold increase in BAL cell GSH levels at 60 min in wild-type mice; however, GSH levels only increased by 40% in the plasma, 60% in the lung, 50% in the ELF, and twofold in the BAL cells within the gut-corrected Cftr KO-Tg mice. No change in GSH levels was observed in the uncorrected Cftr KO mice. These studies suggest that CFTR plays an important role in GSH uptake from the diet and transport processes in the lung.

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“…First, fibroblast-mediated release of HGF was greatly potentiated by the presence of plasminogen in the culture environment. Fibroblasts are known to produce plasminogen activators (35)(36)(37). Second, exposure of ECM to reagent plasmin leads to HGF release.…”

Section: Discussionmentioning

confidence: 99%

“…The amount of radiolabel released into the media after 6 h of incubation was measured. The addition of plasminogen or cells alone released small amounts of radiolabel from the ECM ( Figure 2A); however, when NIH3T3 cells (which are known to produce uPA [35][36][37]) and plasminogen were combined, the release of radioactivity from the matrices increased in a plasminogen dosedependent fashion. Extending the incubation time of cells plus 10 g/ml plasminogen to 24 h caused release of greater than 90% of the bound radioactivity (data not shown).…”

Section: Release Of 125 I-hgf From Ecm By Nih3t3 Cellsmentioning

confidence: 99%

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

Matsuoka

Sisson

Nishiuma

et al. 2006

Am J Respir Cell Mol Biol

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Interventions that enhance plasminogen activation within the lung consistently limit the fibrosis that follows alveolar injury. However, this protective effect cannot be attributed solely to accelerated clearance of fibrin that forms as a provisional matrix after lung injury. To explore other mechanisms, we considered interactions between the plasminogen activation system and hepatocyte growth factor (HGF). HGF is known to have antifibrotic activity, but to do so, it must be both released from its sites of sequestration within extracellular matrix (ECM) and activated by proteolytic cleavage. A recent study using bleomycin-exposed mice showed that manipulations of the plasminogen activation system influenced the amount of free HGF within bronchoalveolar lavage fluid without affecting total lung HGF mRNA or protein. To elucidate the mechanisms, we studied the role of plasminogen activation in fibroblastmediated HGF release and activation. We found that NIH3T3 and mouse lung fibroblasts release ECM-bound HGF in a plasminogendependent fashion. The plasminogen effect was lost when lung fibroblasts from urokinase-type plasminogen activator (uPA)-deficient mice were used, and was increased by fibroblasts from plasminogen activator inhibitor (PAI)-1-deficient mice. Plasminogen addition to NIH3T3 or mouse lung fibroblasts increased conversion of pro-HGF to its active form. The plasminogen effect on activation was lost when uPA-deficient fibroblasts were used and accentuated by PAI-1-deficient fibroblasts. In conjunction with the previous in vivo study, these results suggest that plasminogen activation can protect the lung against fibrosis by increasing the availability of active HGF.

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Glutathione restores collagen degradation in TGF-β-treated fibroblasts by blocking plasminogen activator inhibitor-1 expression and activating plasminogen

Abstract: restores collagen degradation in TGF-␤-treated fibroblasts by blocking plasminogen activator inhibitor-1 expression and activating plasminogen.

Cited by 32 publications

References 76 publications

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

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