Spleen tyrosine kinase (Syk) inhibitor fostamatinib limits tissue damage and fibrosis in a bleomycin-induced scleroderma mouse model.

Abstract

OBJECTIVES:

The pathogenesis of fibrosis in scleroderma (SSc) is unknown. TGF-β 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 tyro-sine 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-β expression decreased in both skin and lung tissues.

CONCLUSIONS:

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-β expression. The Syk pathway appears as a potential molecular target for therapeutic intervention in SSc.

• Authors: Omer Nuri Pamuk, Guray Can, Suleyman Ayvaz, Turan Karaca, Gulsum Emel Pamuk, Selim Demirtas, George C Tsokos
• Journal: Clinical and experimental rheumatology (Clin Exp Rheumatol) 2015 Jul-Aug Vol. 33 Issue 4 Suppl 91 Pg. S15-22 ISSN: 0392-856X [Print] Italy
• PMID: 26148346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Intracellular Signaling Peptides and Proteins
• Morpholines
• Oxazines
• Protein Kinase Inhibitors
• Pyridines
• Pyrimidines
• Receptors, Fc
• Transforming Growth Factor beta
• Bleomycin
• Immunoglobulin E
• Protein-Tyrosine Kinases
• Syk Kinase
• Syk protein, mouse
• fostamatinib

Topics

• Aminopyridines
• Animals
• Bleomycin
• Cytoprotection
• Disease Models, Animal
• Immunoglobulin E (metabolism)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Lung (drug effects, enzymology, immunology, pathology)
• Mast Cells (drug effects, immunology, metabolism)
• Mice, Inbred C57BL
• Morpholines
• Oxazines (pharmacology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pulmonary Fibrosis (chemically induced, enzymology, immunology, pathology, prevention & control)
• Pyridines (pharmacology)
• Pyrimidines
• Receptors, Fc (metabolism)
• Scleroderma, Systemic (chemically induced, enzymology, immunology, pathology, prevention & control)
• Signal Transduction (drug effects)
• Skin (drug effects, enzymology, immunology, pathology)
• Syk Kinase
• Transforming Growth Factor beta (metabolism)