The Impact of Smad3 Loss of Function on TGF-β Signaling and Radiation-Induced Capsular Contracture

Department of Biomedical Engineering (School of Engineering), University of Rochester, Rochester, New York, United States
Plastic and Reconstructive Surgery (Impact Factor: 2.99). 06/2011; 127(6):2263-9. DOI: 10.1097/PRS.0b013e3182131bea
Source: PubMed


Capsular contracture remains a major problem following prosthetic breast implantation, especially in patients undergoing irradiation. Recent studies suggest that such radiation injuries are a cascading process of cytokine activation, with transforming growth factor (TGF)-β acting as the "master switch." Because TGF-β signals through phosphorylation of Smad3, a plausible approach to abate TGF-β-induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wild-type and Smad3 knockout mice was compared using micro-computed tomographic and histologic examination.
On day 0, 48 mice were implanted with bilateral silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomographic scanning. Animals in the radiation arm then received a 10-Gy directed radiation dose. On postoperative days 21, 28, 35, and 42, animals were imaged again. Histologic evaluation was performed at necropsy.
Irradiated implants in the wild-type mice demonstrated shape and contour deformation on micro-computed tomographic scanning beginning on postoperative day 21 and progressing through day 42. Conversely, micro-computed tomographic scanning of irradiated implants in knockout mice demonstrated few changes from day 0 through day 42. Corresponding histologic specimens from wild-type mice demonstrated irregular capsules composed of disorganized collagen that became thicker from day 21 to day 42. Irradiated knockout specimen maintained thin capsules from day 21 through day 42.
In this work, inhibiting TGF-β signaling led to a reduction in radiation-induced capsular contracture as measured by micro-computed tomographic and histologic evaluation. The results of this study suggest a promising target for the prevention of capsular contracture through the development of anti-Smad3/TGF-β-based therapies.

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    • "Reported techniques include copious irrigation with sterile normal saline, in situ irrigation with saline followed by antibiotic instillation,4–6 and in situ glucocorticoid instillation.7 Current research focuses on the texturing of implants,8–11 using in situ biogels and collagen scaffolds to reduce the rate of capsular contraction,9 and limiting the body’s immune response to the implants.10 Additional studies have been reported using rabbits as a model for capsule formation to guide the development of more efficacious breast implants.12 "
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    ABSTRACT: Introduction: Capsular contracture is a chronic and the most frequent complication of augmentation mammoplasty with breast implants and the main cause of patient's and surgeon's dissatisfaction. The mammary capsule consists of a fibrous tissue that surrounds the implant that may contract, changing the shape and consistency of the breast. In its advanced stage is accompanied by pronounced deformity, hardness and pain, being indicated for surgical treatment. Material and methods: All the articles indexed on PubMed through the search 'capsular contracture' (2000 - January 2012) were reviewed and were included the articles of greater interest in terms of etiology, prophylaxis and treatment. Articles referred in relevant publications were also examined. Results: Everything indicates that its etiology is multifactorial; the etiopathology of breast capsular contracture continues being subject of multiple pre-clinical investigations. There are many studies performed in order to prevent the onset of capsular contracture but, although promising results, little is set for its application on clinical practice. The capsulectomy/capsulotomy continues being the gold standard treatment although the future may undergo non invasive techniques, at least in mild stages of disease. Conclusion: Although the surgical techniques and the quality of breast implants have been improving drastically in recent years, capsular contracture remains a real complication with great incidence and that continues affecting thousands of women all over the world.
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