Alpha1-Antitrypsin Mitigates Radiation-Induced Capsular Contracture and Fibrosis In-Vivo
Idan Farber, Yuval Anav, Dor Halpern, Lihie Sheffer, Oron Goldstein, Meir Retchkiman, Yuval Krieger, Navit Ogen-Shtern, Samuel Cohen, Sabri El-Saied, Eli C Lewis, Eldad SilbersteinIntroduction:
Capsular contracture remains a significant complication after alloplastic breast reconstruction, particularly following post-mastectomy radiotherapy. This study evaluated the therapeutic potential of human alpha-1 antitrypsin (hAAT) in reducing radiation-associated capsular fibrosis.
Methods:
Textured silicone-discs were implanted subcutaneously in female C57BL/6 mice on day 0, followed immediately by localized 15 Gy irradiation of the implantation site. Mice were assigned to non-irradiated controls, irradiated albumin-treated controls, or irradiated hAAT-treated groups. Albumin control or hAAT was administered locally on days 0, 3, and 6. Capsule formation was assessed by MRI on day 21. Explants were collected on days 14 and 21 for histology, and day-21 tissues were further analyzed by gene expression profiling of inflammatory and fibrotic mediators. Human dermal fibroblasts were used to assess hAAT effects on radiation-associated TGFβ expression in vitro.
Result:
Irradiated controls developed significant capsule thickening, disorganized collagen deposition, and inflammatory infiltration compared with non-irradiated controls. In contrast, hAAT-treated irradiated mice demonstrated capsule thickness comparable to non-irradiated controls, with improved extracellular matrix organization and reduced inflammation. hAAT treatment reduced interleukin-1 beta (IL-1β), transforming growth factor beta (TGFβ), and collagen type I expression, increased the interleukin-1 receptor antagonist/interleukin-1 beta (IL-1Ra/IL-1β) ratio, and upregulated Sloan-Kettering Institute proto-oncogene (SKI) expression, resulting in predominance of SKI over TGFβ compared with irradiated controls. In a separate in-vitro human dermal fibroblast model, hAAT attenuated radiation-induced TGFβ upregulation.
Conclusion:
Local hAAT treatment may reduce early radiation-associated peri-silicone inflammation and fibrotic capsule formation, supporting its further investigation as a prophylactic strategy in implant-based reconstruction.