Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis

Annals of the Rheumatic Diseases

Volumn 76, Issue 11, 2017, Pages 1941-1948

  Huang, Jingang ^a   Maier, Christiane ^a   Zhang, Yun ^a   Soare, Alina ^a   Dees, Clara ^a   Beyer, Christian ^a   Harre, Ulrike ^a   Chen, Chih Wei ^a   Distler, Oliver ^b   Schett, Georg ^a   Wollin, Lutz ^c   Distler, Jörg H W ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^b UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^c BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

Author keywords

CSF; endothelial; macrophages; scleroderma; VEGF

Indexed keywords

NINTEDANIB; TRANSCRIPTION FACTOR FRA 2; VASCULOTROPIN; ENZYME INHIBITOR; FOSL2 PROTEIN, MOUSE; INDOLE DERIVATIVE; PROTEIN TYROSINE KINASE; VASCULOTROPIN A;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; BIOACCUMULATION; BLOOD VESSEL OCCLUSION; CAPILLARY ENDOTHELIAL CELL; CELL DIFFERENTIATION; CELL POLARITY; CELL PROLIFERATION; CONTROLLED STUDY; DRUG MECHANISM; EXTRACELLULAR MATRIX; FIBROBLAST; FIBROSIS; HEART MUSCLE FIBROSIS; HUMAN; HUMAN CELL; LUNG FIBROSIS; MACROPHAGE; MACROPHAGE ACTIVATION; MICROANGIOPATHY; MONOCYTE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PULMONARY HYPERTENSION; SKIN FIBROSIS; SYSTEMIC SCLEROSIS; TRANSGENIC MOUSE; VASCULAR DISEASE; VASCULAR SMOOTH MUSCLE CELL; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; COMPLICATION; CYTOLOGY; DISEASE MODEL; DRUG EFFECTS; HYPERTENSION, PULMONARY; PATHOLOGY; PULMONARY ARTERY; SCLERODERMA, SYSTEMIC; VASCULAR SMOOTH MUSCLE;

ANIMALS; CELL PROLIFERATION; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; FIBROSIS; FOS-RELATED ANTIGEN-2; HYPERTENSION, PULMONARY; INDOLES; MACROPHAGE ACTIVATION; MICE; MICE, TRANSGENIC; MUSCLE, SMOOTH, VASCULAR; PROTEIN-TYROSINE KINASES; PULMONARY ARTERY; SCLERODERMA, SYSTEMIC; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 85031008231     PISSN: 00034967     EISSN: 14682060     Source Type: Journal    
DOI: 10.1136/annrheumdis-2016-210823     Document Type: Article

References (43)

1. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009;360:1989-2003.
2. R amming A, Dees C, Distler JH. From pathogenesis to therapy-Perspective on treatment strategies in fibrotic diseases. Pharmacol Res 2015;100:93-100.
3. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008;68:4774-82.
4. T andon F, Herrmann E, Ayaub P, et al. Nintedanib attenuates the polarization of profibrotic macrophages through the inhibition of tyrosine phosphorylation on CSF1 receptor K. Am J Respir Crit Care Med 2017;195:A2397.
5. D istler O, Distler JH, Scheid A, et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res 2004;95:109-16.
6. O lson LE, Soriano P. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 2009;16:303-13.
7. Maurer B, Distler A, Suliman YA, et al. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Ann Rheum Dis 2014;73:1880-7.
8. Skhirtladze C, Distler O, Dees C, et al. Src kinases in systemic sclerosis: central roles in fibroblast activation and in skin fibrosis. Arthritis Rheum 2008;58:1475-84.
9. Huang J, Beyer C, Palumbo-Zerr K, et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016;75:150.3-1.
10. Yoo SY, Kwon SM. Angiogenesis and its therapeutic opportunities. Mediators Inflamm 2013;2013:1-11.
11. D istler JH, Hirth A, Kurowska-Stolarska M, et al. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003;47:149-61.
12. R icheldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
13. Maurer B, Busch N, Jungel A, et al. Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis the transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Circulation 2009;120:2367-76.
14. Maurer B, Reich N, Juengel A, et al. Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Ann Rheum Dis 2012;71:1382-7.
15. R eich N, Maurer B, Akhmetshina A, et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum 2010;62:280-90.
16. Eferl R, Hasselblatt P, Rath M, et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Natl Acad Sci U S A 2008;105:10525-30.
17. Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical wnt signalling is required for TGF-â-mediated fibrosis. Nat Commun 2012;3:735.
18. D ees C, Akhmetshina A, Zerr P, et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med 2011;208:961-72.
19. P alumbo-Zerr K, Zerr P, Distler A, et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-Â signaling and fibrosis. Nat Med 2015;21:150-8.
20. Avouac J, Palumbo K, Tomcik M, et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor â-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum 2012;64:1642-52.
21. Venalis P, Kumánovics G, Schulze-Koops H, et al. Cardiomyopathy in murine models of systemic sclerosis. Arthritis Rheumatol 2015;67:508-16.
22. P ietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43(12 Suppl S):S25-S32.
23. Maurer B, Distler A, Dees C, et al. Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors. Ann Rheum Dis 2013;72:2039-46.
24. D orfmöller P, Humbert M, Capron F. [Update on the pathomorphological assessment of vasculopathies in pulmonary arterial hypertension]. Pathologe 2006;27:140-6.
25. al-Sabbagh MR, Steen VD, Zee BC, et al. Pulmonary arterial histology and morphometry in systemic sclerosis: A case-control autopsy study. J Rheumatol 1989;16:1038-42.
26. P alumbo-Zerr K, Zerr P, Distler A, et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-â signaling and fibrosis. Nat Med 2015;21:150-8.
27. D istler JH, Jöngel A, Pileckyte M, et al. Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis Rheum 2007;56:4203-15.
28. N akamura M, Hamada M, Hasegawa K, et al. c-Maf is essential for the F4/80 expression in macrophages in vivo. Gene 2009;445:66-72.
29. Barros MH, Hauck F, Dreyer JH, et al. Macrophage polarisation: An immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One 2013;8:e80908.
30. Schett G. Review: immune cells and mediators of inflammatory arthritis. Autoimmunity 2008;41:224-9.
31. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 2010;30:245-57.
32. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 2016;44:450-62.
33. D istler O, Distler JH. Tocilizumab for systemic sclerosis: implications for future trials. Lancet 2016;387:2580-1.
34. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial. Lancet 2016;387:2630-40.
35. Akhmetshina A, Dees C, Pileckyte M, et al. Dual inhibition of c-Abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. Faseb J 2008;22:2214-22.
36. Akhmetshina A, Venalis P, Dees C, et al. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum 2009;60:219-24.
37. D istler JH, Jöngel A, Huber LC, et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007;56:311-22.
38. P yonteck SM, Akkari L, Schuhmacher AJ, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013;19:1264-72.
39. Goldthorpe H, Jiang JY, Taha M, et al. Occlusive lung arterial lesions in endothelialtargeted, fas-induced apoptosis transgenic mice. Am J Respir Cell Mol Biol 2015;53:712-8.
40. D ees C, Schlottmann I, Funke R, et al. The wnt antagonists DKK1 and SFRP1 are downregulated by promoter Hypermethylation in systemic sclerosis. Ann Rheum Dis 2014;73:1232-9.
41. Moldovan L, Moldovan NI. Role of monocytes and macrophages in angiogenesis. Exs 2005;94:127-46.
42. R iabov V, Gudima A, Wang N, et al. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 2014;5:75.
43. O kazaki T, Ebihara S, Takahashi H, et al. Macrophage colony-stimulating factor induces vascular endothelial growth factor production in skeletal muscle and promotes tumor angiogenesis. J Immunol 2005;174:7531-8.