Spleen tyrosine kinase (Syk) inhibitor fostamatinib limits tissue damage and fibrosis in a bleomycin-induced scleroderma mouse model
Küçük Resim Yok
Tarih
2015
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Clinical & Exper Rheumatology
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Objective. The pathogenesis of fibrosis in scleroderma (SSc) is unknown. TGF-beta and platelet-derived growth factor are important in the development of fibrosis and tyrosine kinases are involved in these pathways. The possible antifibrotic effects of various kinase inhibitors in SSc have been studied before. Spleen tyrosine kinase (Syk) is a protein tyrosine kinase which activates intracellular signal transduction pathways; and has been claimed to be involved in the pathogenesis of systemic autoimmune diseases. Inhibition of Syk suppresses IgE-and IgG-associated FcR signal activation in various cell types; and suppresses experimental arthritis and skin and kidney disease in lupus-prone mice. We investigated the ability of a small drug, the Syk inhibitor, fostamatinib, to protect mice from bleomycin-induced SSc. Methods. Four study groups of BALB/c mice were included into this study: control, bleomycin (administered subcutaneously to BALB/c mice for 21 days), bleomycin and fostamatinib (mice fed with chow containing a Syk inhibitor for 21 days), and fostamatinib alone groups. Skin and lung tissue specimens were obtained and evaluated histologically. Results. Treatment with fostamatinib significantly reduced skin thickness and fibrosis. Mice treated with fostamatinib also displayed less fibrosis and inflammation in the lung tissue. Following fostamatinib treatment, Syk, phospho-Syk, and TGF-beta expression decreased in both skin and lung tissues. Conclusion. The Syk inhibitor fostamatinib prevented bleomycin-induced fibrosis and inflammation in the skin and in the lung. The anti-fibrotic effect of fostamatinib is linked to reduced Syk phosphorylation and TGF-beta expression. The Syk pathway appears as a potential molecular target for therapeutic intervention in SSc.
Açıklama
Anahtar Kelimeler
Scleroderma, Bleomycin, Fostamatinib, Fibrosis, Growth-Factor-Beta, Systemic-Sclerosis, Imatinib Mesylate, Extracellular-Matrix, Disease Progression, Open-Label, Therapy, Skin, Phase, Cells
Kaynak
Clinical And Experimental Rheumatology
WoS Q Değeri
Q2
Scopus Q Değeri
Q2
Cilt
33
Sayı
4
