A decision support system for primary headache developed through machine learning.

OBJECTIVES

To examine the effects of simultaneous inhibition of c-Abl and Src kinases on the gene expression and in vitro production of profibrotic molecules by dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) of recent onset.

METHODS

Dermal fibroblasts from normal individuals or from patients with diffuse cutaneous SSc fulfilling the American College of Rheumatology/EULAR SSc classification criteria were cultured in media containing increasing concentrations of the dual c-Abl and Src kinase inhibitor Bosutinib for 24 h. Total soluble collagen in cell culture supernatants was quantified. Western blots were performed for quantitative assessment of type I collagen, fibronectin, and α-smooth muscle actin (α-SMA) production. Quantitative PCR was performed to examine the effects of Bosutinib on the expression of profibrotic and TGF-β-responsive genes in cultured SSc dermal fibroblasts.

RESULTS

Simultaneous inhibition of c-Abl and Src kinases with Bosutinib reduced the expression of numerous fibrosis-associated genes including COL1A1, COL1A3, FN, and TGFβ and the production of the corresponding proteins by SSc dermal fibroblasts. Bosutinib also decreased the transition of normal dermal fibroblasts into activated myofibroblasts induced by TGF-β as evidenced by reduction of α-SMA in cell extracts from normal and SSc dermal fibroblasts.

CONCLUSIONS

Simultaneous inhibition of c-Abl and Src kinases with Bosutinib abrogates the exaggerated expression of genes encoding fibrillar collagens, fibronectin, and TGF-β-responsive genes and reduces type I collagen, fibronectin and α-SMA production by SSc dermal fibroblasts in vitro. Bosutinib also abrogates TGF- β-induced transition of normal fibroblasts to activated myofibroblasts. These results indicate that inhibition of c-Abl and Src kinases activity may be an effective disease modifying antifibrotic therapeutic intervention for SSc.