Upregulation of urokinase in alveolar macrophages and lung tissue in response to silica particles

Lardot, C.; Delos, Monique; Lison, Dominique

doi:10.1152/ajplung.1998.274.6.l1040

Cited by 12 publications

(12 citation statements)

References 31 publications

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“…In one report a similar finding has been shown for the expression of urokinase-type plasminogen activators (uPAs) during experimental silicosis. 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).…”

Section: Discussionmentioning

confidence: 78%

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: 78%

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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“…The uPA/plasmin system is pivotal for leukocyte migration and turnover and growth of pathogens. Mice lacking the uPA gene exhibit an accelerated fibrotic response postchallenge with mineral and silica particles (41,42). uPA is shown to be an important participant in host defense against opportunistic pathogens, such as Pneumocystis carinii, suggesting its critical role in the network of inflammatory events (2,6,21).…”

mentioning

confidence: 99%

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

Chen

Zhao

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na(+) flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na(+)-K(+)-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA(-/-) mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na(+)-K(+)-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function.

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“…However, macrophages can also express molecules that inhibit fibrosis and promote repair in the proper milieu. These include substances that promote the clearance of fibrin matrix (such as uPa) (7)(8)(9) and down-regulate inflammation, fibroblast proliferation, and collagen deposition (such as PGE 2 ) (10 -14).…”

mentioning

confidence: 99%

GM-CSF Regulates Bleomycin-Induced Pulmonary Fibrosis Via a Prostaglandin-Dependent Mechanism

Moore

Coffey

Christensen

et al. 2000

The Journal of Immunology

135

110

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To characterize the role of GM-CSF in pulmonary fibrosis, we have studied bleomycin-induced fibrosis in wild-type mice vs mice with a targeted deletion of the GM-CSF gene (GM-CSF−/− mice). Without GM-CSF, pulmonary fibrosis was worse both histologically and quantitatively. These changes were not related to enhanced recruitment of inflammatory cells because wild-type and GM-CSF−/− mice recruited equivalent numbers of cells to the lung following bleomycin. Interestingly, recruitment of eosinophils was absent in GM-CSF−/− mice. We investigated whether the enhanced fibrotic response in GM-CSF−/− animals was due to a deficiency in an endogenous down-regulator of fibrogenesis. Analysis of whole lung homogenates from saline- or bleomycin-treated mice revealed that GM-CSF−/− animals had reduced levels of PGE2. Additionally, alveolar macrophages were harvested from wild-type and GM-CSF−/− mice that had been exposed to bleomycin. Although bleomycin treatment impaired the ability of alveolar macrophages from wild-type mice to synthesize PGE2, alveolar macrophages from GM-CSF−/− mice exhibited a significantly greater defect in PGE2 synthesis than did wild-type cells. Exogenous addition of GM-CSF to alveolar macrophages reversed the PGE2 synthesis defect in vitro. Administration of the PG synthesis inhibitor, indomethacin, to wild-type mice during the fibrogenic phase postbleomycin worsened the severity of fibrosis, implying a causal role for PGE2 deficiency in the evolution of the fibrotic lesion. These data demonstrate that GM-CSF deficiency results in enhanced fibrogenesis in bleomycin-induced pulmonary fibrosis and indicate that one mechanism for this effect is impaired production of the potent antifibrotic eicosanoid, PGE2.

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Upregulation of urokinase in alveolar macrophages and lung tissue in response to silica particles

Cited by 12 publications

References 31 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

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

GM-CSF Regulates Bleomycin-Induced Pulmonary Fibrosis Via a Prostaglandin-Dependent Mechanism

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