We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
S.10.1 FRA-2 transgenic mice display the main features of SSC-associated pulmonary hypertension in a PDGF-BB/PDGFR pathway dependent manner.
- Authors
Maurer, B.; Reich, N.; Jüngel, A.; Kriegsmann, J.; Gay, R. E.; Schett, G.; Michel, B. A.; Gay, S.; Distler, J.; Distler, O.
- Abstract
Objectives. SSc-related pulmonary hypertension (PH), though sharing similarities, substantially differs from idiopathic PAH (IPAH) and might warrant different therapeutic approaches. However, research is hampered by the lack of biosamples of SSc patients and of suitable pre-clinical models. Herein, we evaluated the Fra-2 transgenic (tg) mice as a novel animal model for SSc-associated PH.Methods. Lung sections of Fra-2 tg (n = 12) and wild-type (wt) mice (n = 6) were analysed at 16 weeks of age by histology and immunohistochemistry. To test the model's sensitivity to change over treatment, Fra-2 tg mice (n = 6) were treated with the tyrosine kinase inhibitor nilotinib at 2 × 37.5 mg/day by oral gavage from 8 weeks of age.Results. Fra-2 tg mice developed ILD with inflammatory infiltrates consisting of macrophages (F40/80+) and lymphocytes (CD3+) and fibrosis as analysed by Masson's trichrome staining. Severe remodelling of pulmonary arteries with increase in vessel wall thickness [median (Q1, Q3) 44 (32, 59) vs 21.5 (13, 36) μm; P < 0.05] and occlusion of pulmonary arteries [33 (33, 53) vs 0 (0, 1)%; P < 0.05] occurred. Fra-2 tg mice developed features more common in SSc-associated PAH than in IPAH including intimal thickening with mainly concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis. Intimal thickening occurred due to proliferation (PCNA+) of myofibroblasts (αSMA+/SM22α−) and not vascular smooth muscle cells (αSMA+/SM22α+). In pulmonary vessels of Fra-2 tg compared with wt mice, the expression of PDGF-BB [median (Q1, Q3) of staining intensity 3 (2.8, 3.0) vs 0 (0, 1); P < 0.05] and the phosphorylated (= activated) PDGFRβ [3 (2, 3) vs 0 (0.0, 0.3); P < 0.05] was up-regulated. Additionally, in Fra-2 tg mice, tissue macrophages showed an increased staining intensity for PDGF-BB and p-PDGFRβ. Thus, these findings suggest a potential role for PDGF-BB in the pulmonary pathophysiology of Fra-2 tg mice. Targeting the PDGF-BB/PDGFR pathway by nilotinib largely prevented the vascular remodelling. Compared with vehicle-treated Fra-2 tg mice, the thickness of vessel walls [median (Q1, Q3) 44 (32, 59) vs 22.5 (18, 28) μm; P < 0.05] and the percentage of obliterated vessels [33 (13, 53) vs 0 (0, 7)%; P < 0.05] was decreased by nilotinib. This was parallelled by reduced numbers of proliferating αSMA+ cells [median (Q1, Q3) 22(19, 43) vs 87 (57, 90) PCNA+ vascular cells/HPF]. The vascular expression of p-PDGFRβ and PDGF-BB was decreased in nilotinib compared with vehicle-treated mice indicating successful targeting of this pathway. Nilotinib also inhibited the development of lung fibrosis.Conclusions. Our study suggests the model of Fra-2 transgenic mice as an animal model of SSc-associated PH that displays the main characteristic features of the human disease and that therefore allows studying pathophysiological aspects and might serve as a pre-clinical model for proof of interventional concept studies.
- Subjects
ANIMAL experimentation; CELL receptors; CELLULAR signal transduction; CONFERENCES &; conventions; FIBROBLASTS; IMMUNOHISTOCHEMISTRY; MICE; PLATELET-derived growth factor; SYSTEMIC scleroderma
- Publication
Rheumatology, 2012, Vol 51, Issue suppl_2, pii19
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/ker478