Discovery of Novel Small Molecules that Block Myofibroblast Formation: Implications for Capsular Contracture Treatment.

ABSTRACT

Capsular contracture is a devastating complication that occurs in patients undergoing implant-based breast reconstruction. Ionizing radiation drives and exacerbates capsular contracture in part by activating cytokines, including transforming growth factor-beta (TGF-ß). TGF-ß promotes myofibroblast differentiation and proliferation, leading to excessive contractile scar formation. Therefore, targeting the TGF-ß pathway may attenuate capsular contracture. METHODS: A 20,000 small molecule library was screened for anti-TGF-ß activity. Structurally diverse anti-TGF-ß agents were identified and then tested on primary human capsular fibroblasts. Fibroblasts were irradiated or not, and then treated with both TGF-ß and candidate molecules. Resulting cells were then analyzed for myofibroblast activity using myofibroblast markers including alpha-smooth muscle actin, collagen I, Thy1, and periostin, using Western Blot, quantitative real-time polymerase chain reaction, and immunofluorescence. RESULTS: Human capsular fibroblasts treated with TGF-ß showed a significant increase in alpha-smooth muscle actin, collagen I, and periostin levels (protein and/or mRNA). Interestingly, fibroblasts treated with latent TGF-ß and 10 Gy radiation also showed significantly increased levels of myofibroblast markers. Cells that were treated with the novel small molecules showed a significant reduction in myofibroblast activation, even in the presence of radiation. CONCLUSIONS: Several novel small molecules with anti-TGF-ß activity can effectively prevent human capsular fibroblast to myofibroblast differentiation in vitro, even in the presence of radiation. These results highlight novel therapeutic options that may be utilized in the future to prevent radiation-induced capsular contracture.