Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma?

Manetti, Mirko; Rosa, Irene; Milia, Anna Franca; Guiducci, Serena; Carmeliet, Peter; Ibba‐Manneschi, Lidia; Matucci‐Cerinic, Marco

doi:10.1136/annrheumdis-2013-203706

Cited by 76 publications

(74 citation statements)

References 44 publications

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“…15 Lungs from uPAR( À / À ) mice displayed nonspecific interstitial pneumonia-like pathological features, with a significant increase in alveolar septal width and collagen content. 36 These studies suggest that downregulation of uPAR may be related with interstitial pulmonary fibrosis; however, the uPAR-initiated EMT in small airway of COPD patients may be accounting for small airway fibrosis in COPD. It is of interest that this phenomenon may be associated with pathological characteristics of different regions in COPD.…”

Section: Discussionmentioning

confidence: 99%

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Wang

Zhang

et al. 2015

Laboratory Investigation

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Urokinase-type plasminogen activator (uPA) augments inflammation and tissue remodeling during lung injury and repair. The uPA expression in small airway epithelium of chronic obstructive pulmonary disease (COPD) increases. Epithelialmesenchymal transition (EMT) is important in the small airway fibrosis of COPD. This study shows the uPA regulation in cigarette smoke extract (CSE)-induced EMT in human small airway epithelial cell lines (HSAEpiCs). uPA is overexpressed in the small airway epithelium of COPD patients and CSE-treated cell lines. Furthermore, uPA expression correlated with vimentin expression in the small airway epithelium of COPD patients. uPA inhibition blocks CSE-induced EMT by reversing E-cadherin and a-catenin expression and retarding the induction of N-cadherin and vimentin, resulting in reduction in migration. uPA overexpression in HSAEpiC cells also promotes EMT and migration. EMT is partly reversed in uPA-overexpressing HSAEpiC cells through the silencing expression of uPA receptor. In conclusion, this study provides new insights into the contribution of uPA upregulation to EMT associated with small airway remodeling in COPD.

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Section: Discussionmentioning

confidence: 99%

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Wang

Zhang

et al. 2015

Laboratory Investigation

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“…This hypothesis has been supported by the observation that uPAR deletion induces, in a murine model, pulmonary fibrosis and peripheral microvasculopathy (58). On this basis, we also investigated whether SSc fibroblasts, which show an increased membrane expression of cleaved uPAR, exhibited characteristics suggesting a myofibroblast transition.…”

Section: Discussionmentioning

confidence: 76%

Upregulation of the N-Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts

Rossi

Napolitano

Pesapane

et al. 2015

The Journal of Immunology

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Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis. N-Formyl peptide (fMLF) receptors (FPRs) are chemotactic receptors involved in inflammation. Three FPRs have been identified: FPR1, FPR2, and FPR3. We have examined, by RT-PCR, Western blot and immunohistochemistry, FPRs expression in skin fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibroblasts. Several functions of FPRs occur through the interaction with a region of the urokinase-type plasminogen activator receptor (uPAR88–92), able to interact with FPRs and to mediate urokinase (uPA) or fMLF-dependent cell migration. Soluble uPAR84–95 peptide can act as a direct ligand of FPRs. Furthermore, uPA or its aminoterminal fragment (ATF) can promote the exposure of the uPAR88–92 region. The WKYMVm peptide is a FPRs pan-agonist. We investigated the functional effects of these agonists on normal and SSc fibroblasts. ATF, uPAR84–95, and WKYMVm regulated adhesion, migration, and proliferation of normal fibroblasts. Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced, except for the proliferative response to ATF. SSc fibroblasts showed increased α-smooth muscle actin expression and improved capability to induce wound closure. Indeed, they overexpressed a cleaved uPAR form, exposing the uPAR88–92 region, and vitronectin, both involved in fibrosis and in the fibroblast-to-myofibroblast transition. FPR stimulation promoted α-smooth muscle actin expression in normal fibroblasts as well as motility, matrix deposition, αvβ5 integrin expression, and radical oxygen species generation in normal and SSc fibroblasts. This study provides evidence that FPRs may play a role in fibrosis and in the fibroblast-to-myofibroblast transition.

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“…From a respiratory prospective, uPAR 2/2 mice have been shown to develop airway inflammation and fibrosis spontaneously, exemplifying the key role of this receptor in lung homeostasis (2). Therefore, a greater understanding of how this receptor is regulated is warranted and may provide greater insight into both respiratory and other human disorders.…”

Section: Mateusz Siedlinskimentioning

confidence: 99%

Letters to the Editor

Sayers¹,

Portelli²,

Siedliński³

2015

FASEB j.

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Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma?

Abstract: uPAR(-/-) mice are a new animal model closely mimicking the histopathological features of SSc. This model warrants future studies.

Cited by 76 publications

References 44 publications

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Upregulation of the N-Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts

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