title: Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis.
abstract: OBJECTIVE
  Systemic sclerosis-associated pulmonary arterial hypertension differs from idiopathic pulmonary arterial hypertension with respect to histopathology, treatment responses and survival. Medical progress on PAH is hampered by the lack of human biosamples and suitable animal models. In this study, the authors evaluated fos-related antigen 2 (Fra-2) transgenic mice as a novel model for systemic sclerosis-associated pulmonary arterial hypertension.
  
  
  METHODS
  Lung sections of Fra-2 transgenic (n=12) and wild-type mice (n=6) were analysed at 16 weeks by histology using Dana Point criteria. Cellular and molecular key players were assessed by immunohistochemistry. To test the model's sensitivity to change over treatment, a subgroup of Fra-2 transgenic mice (n=6) was treated with the tyrosine kinase inhibitor nilotinib twice daily 37.5 mg orally from 8 weeks of age.
  
  
  RESULTS
  Fra-2 transgenic mice developed severe vascular remodelling of pulmonary arteries and non-specific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension. Histological features typical for systemic sclerosis-associated pulmonary arterial hypertension, such as intimal thickening with concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis, but not pulmonary occlusive venopathy were frequently detected. Platelet-derived growth factor signalling pathways were activated in pulmonary vessels of Fra-2 transgenic compared with wild-type mice. Since treatment with nilotinib strongly prevented the development of proliferative vasculopathy and lung fibrosis, the model proved to be sensitive to treatment.
  
  
  CONCLUSIONS
  This study suggests that Fra-2 transgenic mice as an animal model of systemic sclerosis-associated pulmonary arterial hypertension display main characteristic features of the human disease. It therefore allows studying pathophysiological aspects and might serve as a preclinical model for interventional proof-of-concept studies.
authors.affiliation: Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.forename: Nicole
authors.initials: N
authors.lastname: Reich
authors.forename: Astrid
authors.initials: A
authors.lastname: Juengel
authors.forename: Jörg
authors.initials: J
authors.lastname: Kriegsmann
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051921:Fos-Related Antigen-2 / Q000235:genetics* / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016491:Peripheral Vascular Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000150:complications / Q000378:metabolism / Q000473:pathology*
chemical_list: D004791:Enzyme Inhibitors; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C498826:nilotinib