title: 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: OBJECTIVE
  Urokinase-type plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodelling and angiogenesis. The cleavage/inactivation of uPAR is a crucial step in fibroblast-to-myofibroblast transition and has been implicated in systemic sclerosis (SSc) microvasculopathy. In the present study, we investigated whether uPAR gene inactivation in mice could result in tissue fibrosis and peripheral microvasculopathy resembling human SSc.
  
  
  METHODS
  The expression of the native full-length form of uPAR in human skin biopsies was determined by immunohistochemistry. Skin and lung sections from uPAR-deficient (uPAR(-/-)) and wild-type (uPAR(+/+)) mice at 12 and 24 weeks of age were stained with haematoxylin-eosin, Masson's trichrome and Picrosirius red. Dermal thickness and hydroxyproline content in skin and lungs were quantified. Dermal myofibroblast and microvessel counts were determined by immunohistochemistry for α-smooth muscle actin and CD31, respectively. Endothelial cell apoptosis was assessed by TUNEL/CD31 immunofluorescence assay.
  
  
  RESULTS
  Full-length uPAR expression was significantly downregulated in SSc dermis, especially in fibroblasts and endothelial cells. Dermal thickness, collagen content and myofibroblast counts were significantly greater in uPAR(-/-) than in uPAR(+/+) mice. In uPAR(-/-) mice, dermal fibrosis was paralleled by endothelial cell apoptosis and severe loss of microvessels. Lungs from uPAR(-/-) mice displayed non-specific interstitial pneumonia-like pathological features, both with inflammation and collagen deposition. Pulmonary pathology worsened significantly from 12 to 24 weeks, as shown by a significant increase in alveolar septal width and collagen content.
  
  
  CONCLUSIONS
  uPAR(-/-) mice are a new animal model closely mimicking the histopathological features of SSc. This model warrants future studies.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Manetti
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Rosa
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Anna Franca
authors.initials: AF
authors.lastname: Milia
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Internal Medicine and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Guiducci
authors.affiliation: Laboratory of Angiogenesis and the Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and the Neurovascular Link, Vesalius Research Center, University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ibba-Manneschi
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Internal Medicine and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D058628:Myofibroblasts / Q000473:pathology; D016491:Peripheral Vascular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*
chemical_list: D016207:Cytokines; D055293:Receptors, Urokinase Plasminogen Activator; D003094:Collagen
keywords: Pulmonary Fibrosis; Qualitative research; Systemic Sclerosis