| First Author | Wermuth PJ | Year | 2018 |
| Journal | PLoS One | Volume | 13 |
| Issue | 5 | Pages | e0196559 |
| PubMed ID | 29718973 | Mgi Jnum | J:262887 |
| Mgi Id | MGI:6156182 | Doi | 10.1371/journal.pone.0196559 |
| Citation | Wermuth PJ, et al. (2018) Abrogation of transforming growth factor-beta-induced tissue fibrosis in TBRIcaCol1a2Cre transgenic mice by the second generation tyrosine kinase inhibitor SKI-606 (Bosutinib). PLoS One 13(5):e0196559 |
| abstractText | Transforming growth factor-beta (TGF-beta) plays a crucial role in the pathogenesis of Systemic Sclerosis (SSc) and other fibrotic disorders. TGF-beta-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-beta induced cutaneous and pulmonary fibrosis. For this purpose, we employed the TBRIcaCol1a2Cre transgenic mice expressing an inducible constitutively active TGF-beta 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-beta-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-beta-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. |
