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Deprecated: Implicit conversion from float 278.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 PLoS+One 2018 ; 13 (5): ä Nephropedia Template TP
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Abrogation of transforming growth factor-?-induced tissue fibrosis in TBRIcaCol1a2Cre transgenic mice by the second generation tyrosine kinase inhibitor SKI-606 (Bosutinib) #MMPMID29718973
Wermuth PJ; Jimenez SA
PLoS One 2018[]; 13 (5): ä PMID29718973show ga
Transforming growth factor-? (TGF-?) plays a crucial role in the pathogenesis of Systemic Sclerosis (SSc) and other fibrotic disorders. TGF-?-mediated c-Abl and Src kinase activation induces strong profibrotic cascade signaling. The purpose of this study was to test in vivo the antifibrotic activity of Bosutinib (SKI-606), a second generation c-Abl and Src kinase inhibitor, on TGF-? induced cutaneous and pulmonary fibrosis. For this purpose, we employed the TBRIcaCol1a2Cre transgenic mice expressing an inducible constitutively active TGF-? receptor 1 constitutively activated by Col1a promoter-mediated Cre recombinase. The mice were treated parenterally with 2.5, 5.0 or 10.0 mg/kg/day of Bosutinib for 42 days. Skin and lungs from control and Bosutinib-treated mice (n = 6 per group) were assessed by histopathology, measurement of tissue hydroxyproline content, PCR analysis of tissue fibrosis associated gene expression, and evidence of myofibroblast activation. Mice with constitutive TGF-?-1 signaling displayed severe cutaneous and pulmonary fibrosis. Bosutinib administration decreased collagen deposition and hydroxyproline content in the dermis and lungs in a dose-dependent manner. Bosutinib also reversed the marked increase in profibrotic and myofibroblast activation-associated gene expression. These results demonstrate that constitutive TGF-?-1-signaling-induced cutaneous and pulmonary fibrosis were abrogated in a dose-related manner following parenteral administration of the c-Abl and Src tyrosine kinase inhibitor, Bosutinib. These results indicate that Bosutinib may be a potential therapeutic agent for tissue fibrosis in SSc and other fibroproliferative disorders.