Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis
Identifieur interne : 001B84 ( Istex/Corpus ); précédent : 001B83; suivant : 001B85Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis
Auteurs : Britta Maurer ; Nicole Reich ; Astrid Juengel ; Jörg Kriegsmann ; Renate E. Gay ; Georg Schett ; Beat A. Michel ; Steffen Gay ; Jörg H W. Distler ; Oliver DistlerSource :
- Annals of the Rheumatic Diseases [ 0003-4967 ] ; 2012-08.
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.
Url:
DOI: 10.1136/annrheumdis-2011-200940
Links to Exploration step
ISTEX:B029BB8695D404168905F62883469A110563BD5BLe document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title><author><name sortKey="Maurer, Britta" sort="Maurer, Britta" uniqKey="Maurer B" first="Britta" last="Maurer">Britta Maurer</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Reich, Nicole" sort="Reich, Nicole" uniqKey="Reich N" first="Nicole" last="Reich">Nicole Reich</name><affiliation><mods:affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Juengel, Astrid" sort="Juengel, Astrid" uniqKey="Juengel A" first="Astrid" last="Juengel">Astrid Juengel</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Kriegsmann, Jorg" sort="Kriegsmann, Jorg" uniqKey="Kriegsmann J" first="Jörg" last="Kriegsmann">Jörg Kriegsmann</name><affiliation><mods:affiliation>Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany</mods:affiliation></affiliation></author><author><name sortKey="Gay, Renate E" sort="Gay, Renate E" uniqKey="Gay R" first="Renate E" last="Gay">Renate E. Gay</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Schett, Georg" sort="Schett, Georg" uniqKey="Schett G" first="Georg" last="Schett">Georg Schett</name><affiliation><mods:affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Michel, Beat A" sort="Michel, Beat A" uniqKey="Michel B" first="Beat A" last="Michel">Beat A. Michel</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Gay, Steffen" sort="Gay, Steffen" uniqKey="Gay S" first="Steffen" last="Gay">Steffen Gay</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Distler, Jorg H W" sort="Distler, Jorg H W" uniqKey="Distler J" first="Jörg H W" last="Distler">Jörg H W. Distler</name><affiliation><mods:affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Distler, Oliver" sort="Distler, Oliver" uniqKey="Distler O" first="Oliver" last="Distler">Oliver Distler</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:B029BB8695D404168905F62883469A110563BD5B</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1136/annrheumdis-2011-200940</idno><idno type="url">https://api.istex.fr/document/B029BB8695D404168905F62883469A110563BD5B/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001B84</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001B84</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title><author><name sortKey="Maurer, Britta" sort="Maurer, Britta" uniqKey="Maurer B" first="Britta" last="Maurer">Britta Maurer</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Reich, Nicole" sort="Reich, Nicole" uniqKey="Reich N" first="Nicole" last="Reich">Nicole Reich</name><affiliation><mods:affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Juengel, Astrid" sort="Juengel, Astrid" uniqKey="Juengel A" first="Astrid" last="Juengel">Astrid Juengel</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Kriegsmann, Jorg" sort="Kriegsmann, Jorg" uniqKey="Kriegsmann J" first="Jörg" last="Kriegsmann">Jörg Kriegsmann</name><affiliation><mods:affiliation>Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany</mods:affiliation></affiliation></author><author><name sortKey="Gay, Renate E" sort="Gay, Renate E" uniqKey="Gay R" first="Renate E" last="Gay">Renate E. Gay</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Schett, Georg" sort="Schett, Georg" uniqKey="Schett G" first="Georg" last="Schett">Georg Schett</name><affiliation><mods:affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Michel, Beat A" sort="Michel, Beat A" uniqKey="Michel B" first="Beat A" last="Michel">Beat A. Michel</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Gay, Steffen" sort="Gay, Steffen" uniqKey="Gay S" first="Steffen" last="Gay">Steffen Gay</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Distler, Jorg H W" sort="Distler, Jorg H W" uniqKey="Distler J" first="Jörg H W" last="Distler">Jörg H W. Distler</name><affiliation><mods:affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Distler, Oliver" sort="Distler, Oliver" uniqKey="Distler O" first="Oliver" last="Distler">Oliver Distler</name><affiliation><mods:affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of the Rheumatic Diseases</title><title level="j" type="abbrev">Ann Rheum Dis</title><idno type="ISSN">0003-4967</idno><idno type="eISSN">1468-2060</idno><imprint><publisher>BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><date type="published" when="2012-08">2012-08</date><biblScope unit="volume">71</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1382">1382</biblScope></imprint><idno type="ISSN">0003-4967</idno></series><idno type="istex">B029BB8695D404168905F62883469A110563BD5B</idno><idno type="DOI">10.1136/annrheumdis-2011-200940</idno><idno type="href">annrheumdis-71-1382.pdf</idno><idno type="ArticleID">annrheumdis-2011-200940</idno><idno type="PMID">22523431</idno><idno type="local">annrheumdis;71/8/1382</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0003-4967</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="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.</div></front></TEI><istex><corpusName>bmj</corpusName><author><json:item><name>Britta Maurer</name><affiliations><json:string>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</json:string></affiliations></json:item><json:item><name>Nicole Reich</name><affiliations><json:string>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</json:string></affiliations></json:item><json:item><name>Astrid Juengel</name><affiliations><json:string>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</json:string></affiliations></json:item><json:item><name>Jörg Kriegsmann</name><affiliations><json:string>Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany</json:string></affiliations></json:item><json:item><name>Renate E Gay</name><affiliations><json:string>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</json:string></affiliations></json:item><json:item><name>Georg Schett</name><affiliations><json:string>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</json:string></affiliations></json:item><json:item><name>Beat A Michel</name><affiliations><json:string>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</json:string></affiliations></json:item><json:item><name>Steffen Gay</name><affiliations><json:string>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</json:string></affiliations></json:item><json:item><name>Jörg H W Distler</name><affiliations><json:string>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</json:string></affiliations></json:item><json:item><name>Oliver Distler</name><affiliations><json:string>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</json:string></affiliations></json:item></author><articleId><json:string>annrheumdis-2011-200940</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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.</abstract><qualityIndicators><score>9.145</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>2050</abstractCharCount><pdfWordCount>4145</pdfWordCount><pdfCharCount>29259</pdfCharCount><pdfPageCount>6</pdfPageCount><abstractWordCount>261</abstractWordCount></qualityIndicators><title>Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title><pmid><json:string>22523431</json:string></pmid><refBibs><json:item><author><json:item><name>VD Steen</name></json:item><json:item><name>TA Medsger</name></json:item></author><host><volume>66</volume><author></author><title>Ann Rheum Dis</title></host><title>Changes in causes of death in systemic sclerosis, 1972–2002.</title></json:item><json:item><author><json:item><name>RN Channick</name></json:item><json:item><name>G Simonneau</name></json:item><json:item><name>O Sitbon</name></json:item></author><host><volume>358</volume><author></author><title>Lancet</title></host><title>Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.</title></json:item><json:item><author><json:item><name>R Condliffe</name></json:item><json:item><name>DG Kiely</name></json:item><json:item><name>AJ Peacock</name></json:item></author><host><volume>179</volume><author></author><title>Am J Respir Crit Care Med</title></host><title>Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era.</title></json:item><json:item><author><json:item><name>RE Girgis</name></json:item><json:item><name>SC Mathai</name></json:item><json:item><name>JA Krishnan</name></json:item></author><host><volume>24</volume><author></author><title>J Heart Lung Transplant</title></host><title>Long-term outcome of bosentan treatment in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with the scleroderma spectrum of diseases.</title></json:item><json:item><author><json:item><name>MC Vonk</name></json:item><json:item><name>B Broers</name></json:item><json:item><name>YF Heijdra</name></json:item></author><host><volume>68</volume><author></author><title>Ann Rheum Dis</title></host><title>Systemic sclerosis and its pulmonary complications in The Netherlands: an epidemiological study.</title></json:item><json:item><author><json:item><name>P Dorfmüller</name></json:item><json:item><name>M Humbert</name></json:item><json:item><name>F Perros</name></json:item></author><host><volume>38</volume><pages><last>902</last><first>893</first></pages><author></author><title>Hum Pathol</title></host><title>Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases.</title></json:item><json:item><author><json:item><name>MJ Overbeek</name></json:item><json:item><name>MC Vonk</name></json:item><json:item><name>A Boonstra</name></json:item></author><host><volume>34</volume><author></author><title>Eur Respir J</title></host><title>Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy.</title></json:item><json:item><author><json:item><name>EC Derrett-Smith</name></json:item><json:item><name>CP Denton</name></json:item><json:item><name>S Sonnylal</name></json:item></author><host><volume>21</volume><author></author><title>Curr Opin Rheumatol</title></host><title>Animal models of scleroderma: lessons from transgenic and knockout mice.</title></json:item><json:item><author><json:item><name>KR Stenmark</name></json:item><json:item><name>B Meyrick</name></json:item><json:item><name>N Galie</name></json:item></author><host><volume>297</volume><pages><last>32</last><first>1013</first></pages><author></author><title>Am J Physiol Lung Cell Mol Physiol</title></host><title>Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure.</title></json:item><json:item><author><json:item><name>R Eferl</name></json:item><json:item><name>P Hasselblatt</name></json:item><json:item><name>M Rath</name></json:item></author><host><volume>105</volume><author></author><title>Proc Natl Acad Sci USA</title></host><title>Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1.</title></json:item><json:item><author><json:item><name>B Maurer</name></json:item><json:item><name>N Busch</name></json:item><json:item><name>A Jüngel</name></json:item></author><host><volume>120</volume><author></author><title>Circulation</title></host><title>Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis.</title></json:item><json:item><author><json:item><name>JH Distler</name></json:item><json:item><name>A Jüngel</name></json:item><json:item><name>LC Huber</name></json:item></author><host><volume>56</volume><author></author><title>Arthritis Rheum</title></host><title>Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis.</title></json:item><json:item><author><json:item><name>JL Myers</name></json:item><json:item><name>AL Katzenstein</name></json:item></author><host><volume>54</volume><pages><last>103</last><first>90</first></pages><author></author><title>Histopathology</title></host><title>Beyond a consensus classification for idiopathic interstitial pneumonias: progress and controversies.</title></json:item><json:item><author><json:item><name>GG Pietra</name></json:item><json:item><name>F Capron</name></json:item><json:item><name>S Stewart</name></json:item></author><host><volume>43</volume><pages><last>32</last><first>25</first></pages><author></author><title>J Am Coll Cardiol</title></host><title>Pathologic assessment of vasculopathies in pulmonary hypertension.</title></json:item><json:item><author><json:item><name>D Bouros</name></json:item><json:item><name>AU Wells</name></json:item><json:item><name>AG Nicholson</name></json:item></author><host><volume>165</volume><author></author><title>Am J Respir Crit Care Med</title></host><title>Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome.</title></json:item><json:item><author><json:item><name>M Humbert</name></json:item><json:item><name>G Monti</name></json:item><json:item><name>M Fartoukh</name></json:item></author><host><volume>11</volume><author></author><title>Eur Respir J</title></host><title>Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients.</title></json:item><json:item><author><json:item><name>F Perros</name></json:item><json:item><name>D Montani</name></json:item><json:item><name>P Dorfmüller</name></json:item></author><host><volume>178</volume><author></author><title>Am J Respir Crit Care Med</title></host><title>Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension.</title></json:item><json:item><author><json:item><name>MJ Overbeek</name></json:item><json:item><name>A Boonstra</name></json:item><json:item><name>AE Voskuyl</name></json:item></author><host><volume>13</volume><pages><first>61</first></pages><author></author><title>Arthritis Res Ther</title></host><title>Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study.</title></json:item><json:item><author><json:item><name>RT Schermuly</name></json:item><json:item><name>E Dony</name></json:item><json:item><name>HA Ghofrani</name></json:item></author><host><volume>115</volume><author></author><title>J Clin Invest</title></host><title>Reversal of experimental pulmonary hypertension by PDGF inhibition.</title></json:item><json:item><author><json:item><name>R Souza</name></json:item><json:item><name>O Sitbon</name></json:item><json:item><name>F Parent</name></json:item></author><host><volume>61</volume><pages><first>736</first></pages><author></author><title>Thorax</title></host><title>Long term imatinib treatment in pulmonary arterial hypertension.</title></json:item><json:item><author><json:item><name>RF Spiera</name></json:item><json:item><name>JK Gordon</name></json:item><json:item><name>JN Mersten</name></json:item></author><host><volume>70</volume><author></author><title>Ann Rheum Dis</title></host><title>Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial.</title></json:item><json:item><author><json:item><name>O Distler</name></json:item><json:item><name>J Distler</name></json:item><json:item><name>J Varga</name></json:item></author><host><volume>70</volume><pages><last>4</last><first>233</first></pages><author></author><title>Arthritis Rheum</title></host><title>A multi-center, open-label, proof of concept study of imatinib mesylate demonstrates no benefit for the treatment of fibrosis in patients with early, diffuse systemic sclerosis (abstract)</title></json:item><json:item><author><json:item><name>N Reich</name></json:item><json:item><name>B Maurer</name></json:item><json:item><name>A Akhmetshina</name></json:item></author><host><volume>62</volume><author></author><title>Arthritis Rheum</title></host><title>The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis.</title></json:item><json:item><author><json:item><name>J Avouac</name></json:item><json:item><name>K Palumbo</name></json:item><json:item><name>M Tomcik</name></json:item></author><host><author></author><title>Arthritis Rheum</title></host><title>Inhibition of AP-1 signaling abrogates TGF-ß mediated activation of fibroblasts and prevents experimental fibrosis.</title></json:item><json:item><author><json:item><name>P Angel</name></json:item><json:item><name>M Karin</name></json:item></author><host><volume>1072</volume><author></author><title>Biochim Biophys Acta</title></host><title>The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation.</title></json:item><json:item><author><json:item><name>TL Butler</name></json:item><json:item><name>KR Pennypacker</name></json:item></author><host><volume>12</volume><author></author><title>Gene Expr</title></host><title>The transcriptional response to hypoxic insult controlled by FRA-2.</title></json:item></refBibs><genre><json:string>research-article</json:string></genre><host><volume>71</volume><publisherId><json:string>ard</json:string></publisherId><pages><first>1382</first></pages><issn><json:string>0003-4967</json:string></issn><issue>8</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1468-2060</json:string></eissn><title>Annals of the Rheumatic Diseases</title></host><categories><wos><json:string>science</json:string><json:string>rheumatology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>arthritis & rheumatology</json:string></scienceMetrix></categories><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1136/annrheumdis-2011-200940</json:string></doi><id>B029BB8695D404168905F62883469A110563BD5B</id><score>0.23846123</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/B029BB8695D404168905F62883469A110563BD5B/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/B029BB8695D404168905F62883469A110563BD5B/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/B029BB8695D404168905F62883469A110563BD5B/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><availability><p>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</p></availability><date>2012-04-20</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title><author xml:id="author-1"><persName><forename type="first">Britta</forename><surname>Maurer</surname></persName><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation></author><author xml:id="author-2"><persName><forename type="first">Nicole</forename><surname>Reich</surname></persName><affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</affiliation></author><author xml:id="author-3"><persName><forename type="first">Astrid</forename><surname>Juengel</surname></persName><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation></author><author xml:id="author-4"><persName><forename type="first">Jörg</forename><surname>Kriegsmann</surname></persName><affiliation>Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany</affiliation></author><author xml:id="author-5"><persName><forename type="first">Renate E</forename><surname>Gay</surname></persName><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation></author><author xml:id="author-6"><persName><forename type="first">Georg</forename><surname>Schett</surname></persName><affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</affiliation></author><author xml:id="author-7"><persName><forename type="first">Beat A</forename><surname>Michel</surname></persName><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation></author><author xml:id="author-8"><persName><forename type="first">Steffen</forename><surname>Gay</surname></persName><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation></author><author xml:id="author-9"><persName><forename type="first">Jörg H W</forename><surname>Distler</surname></persName><affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</affiliation></author><author xml:id="author-10"><persName><forename type="first">Oliver</forename><surname>Distler</surname></persName><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation></author></analytic><monogr><title level="j">Annals of the Rheumatic Diseases</title><title level="j" type="abbrev">Ann Rheum Dis</title><idno type="pISSN">0003-4967</idno><idno type="eISSN">1468-2060</idno><imprint><publisher>BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><date type="published" when="2012-08"></date><biblScope unit="volume">71</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1382">1382</biblScope></imprint></monogr><idno type="istex">B029BB8695D404168905F62883469A110563BD5B</idno><idno type="DOI">10.1136/annrheumdis-2011-200940</idno><idno type="href">annrheumdis-71-1382.pdf</idno><idno type="ArticleID">annrheumdis-2011-200940</idno><idno type="PMID">22523431</idno><idno type="local">annrheumdis;71/8/1382</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012-04-20</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>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.</p></abstract></profileDesc><revisionDesc><change when="2012-04-20">Created</change><change when="2012-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/B029BB8695D404168905F62883469A110563BD5B/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">annrheumdis</journal-id><journal-id journal-id-type="nlm-ta">Ann Rheum Dis</journal-id><journal-id journal-id-type="publisher-id">ard</journal-id><journal-title>Annals of the Rheumatic Diseases</journal-title><abbrev-journal-title abbrev-type="publisher">Ann Rheum Dis</abbrev-journal-title><abbrev-journal-title>Ann Rheum Dis</abbrev-journal-title><issn pub-type="ppub">0003-4967</issn><issn pub-type="epub">1468-2060</issn><publisher><publisher-name>BMJ Publishing Group Ltd and European League Against Rheumatism</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">annrheumdis-2011-200940</article-id><article-id pub-id-type="doi">10.1136/annrheumdis-2011-200940</article-id><article-id pub-id-type="other">annrheumdis;71/8/1382</article-id><article-id pub-id-type="other">annrheumdis;annrheumdis-2011-200940</article-id><article-id pub-id-type="pmid">22523431</article-id><article-id pub-id-type="other">1382</article-id><article-id pub-id-type="other">annrheumdis-2011-200940</article-id><article-categories><subj-group subj-group-type="heading"><subject>Basic and translational research</subject></subj-group><series-title>Extended report</series-title></article-categories><title-group><article-title>Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Maurer</surname><given-names>Britta</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Reich</surname><given-names>Nicole</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Juengel</surname><given-names>Astrid</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kriegsmann</surname><given-names>Jörg</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Gay</surname><given-names>Renate E</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Schett</surname><given-names>Georg</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Michel</surname><given-names>Beat A</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gay</surname><given-names>Steffen</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Distler</surname><given-names>Jörg H W</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Distler</surname><given-names>Oliver</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</aff><aff id="A2"><label>2</label>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</aff><aff id="A3"><label>3</label>Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany</aff><author-notes><corresp><label>Correspondence to</label> Dr Oliver Distler, Center of Experimental Rheumatology, University Hospital Zurich/Zurich Center of Integrative Human Physiology (ZIHP), Zurich 8091, Switzerland; <email xlink:type="simple">oliver.distler@usz.ch</email></corresp></author-notes><pub-date pub-type="ppub"><month>8</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>20</day><month>4</month><year>2012</year></pub-date><volume>71</volume><volume-id pub-id-type="other">71</volume-id><volume-id pub-id-type="other">71</volume-id><issue>8</issue><issue-id pub-id-type="other">annrheumdis;71/8</issue-id><issue-id pub-id-type="other">8</issue-id><issue-id pub-id-type="other">71/8</issue-id><fpage>1382</fpage><history><date date-type="accepted"><day>24</day><month>2</month><year>2012</year></date></history><permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</copyright-statement><copyright-year>2012</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="annrheumdis-71-1382.pdf"></self-uri><abstract><sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title><partName>Extended report</partName></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis</title><partName>Extended report</partName></titleInfo><name type="personal"><namePart type="given">Britta</namePart><namePart type="family">Maurer</namePart><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nicole</namePart><namePart type="family">Reich</namePart><affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Astrid</namePart><namePart type="family">Juengel</namePart><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jörg</namePart><namePart type="family">Kriegsmann</namePart><affiliation>Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Renate E</namePart><namePart type="family">Gay</namePart><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Georg</namePart><namePart type="family">Schett</namePart><affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Beat A</namePart><namePart type="family">Michel</namePart><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steffen</namePart><namePart type="family">Gay</namePart><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jörg H W</namePart><namePart type="family">Distler</namePart><affiliation>Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Oliver</namePart><namePart type="family">Distler</namePart><affiliation>Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><dateIssued encoding="w3cdtf">2012-08</dateIssued><dateCreated encoding="w3cdtf">2012-04-20</dateCreated><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><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.</abstract><relatedItem type="host"><titleInfo><title>Annals of the Rheumatic Diseases</title></titleInfo><titleInfo type="abbreviated"><title>Ann Rheum Dis</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0003-4967</identifier><identifier type="eISSN">1468-2060</identifier><identifier type="PublisherID">ard</identifier><identifier type="PublisherID-hwp">annrheumdis</identifier><identifier type="PublisherID-nlm-ta">Ann Rheum Dis</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>71</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>1382</start></extent></part></relatedItem><identifier type="istex">B029BB8695D404168905F62883469A110563BD5B</identifier><identifier type="DOI">10.1136/annrheumdis-2011-200940</identifier><identifier type="href">annrheumdis-71-1382.pdf</identifier><identifier type="ArticleID">annrheumdis-2011-200940</identifier><identifier type="PMID">22523431</identifier><identifier type="local">annrheumdis;71/8/1382</identifier><accessCondition type="use and reproduction" contentType="copyright">Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</accessCondition><recordInfo><recordContentSource>BMJ</recordContentSource></recordInfo></mods></metadata><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/B029BB8695D404168905F62883469A110563BD5B/annexes/jpeg</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Rhénanie/explor/UnivTrevesV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001B84 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 001B84 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Rhénanie
|area= UnivTrevesV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:B029BB8695D404168905F62883469A110563BD5B
|texte= Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis
}}
| This area was generated with Dilib version V0.6.31. |  |