Angiotensin Converting Enzyme Inhibitor Reduces Radiation Induced Fibrosis in Peri-Capsular Implant

Abstract

Radiotherapy after implant-based breast reconstruction can cause fibrosis and contracture in the capsule around the implant that may lead to deterioration of the cosmetic result, pain and tenderness and the need for a second surgery. Angiotensin converting enzyme (ACE) inhibitors reduce fibrosis by suppressing angiotensin-II synthesis and TGF-β pathway. In our study, the efficacy ACE inhibitor (Ramipril), on radiation induced capsular fibrosis was evaluated. Thirty Wistar rats in 5 groups were used. Group 1: implant; Group 2: implant + radiation; Group 3: ramipril + implant; Group 4: ramipril + implant + radiation; Group 5: sham. Ramipril treatment was started 5 days before surgery and continued for 12 weeks after surgery. A mini silicone implant was placed in the back of the rats. Single fraction of 21.5 Gy radiation was applied. Tissues were examined histologically and immunohistochemically (TGF- β1, MMP-2, TIMP-2 expression). The alteration of plasma TGF-β1 levels were examined before and after the experiment. After applying implant or implant + radiation, capsular thickness, percentage of fibrotic area, tissue and plasma TGF-β1 levels significantly increased and MMP-2/TIMP-2 ratio significantly decreased compared to sham group. In ramipril treated groups, the decrease in capsular thickness, fibrosis, TGF-β1 positivity, and increase in MMP-2 /TIMP-2 ratio was found to be significant. In ramipril + implant + radiation group, the alteration values of TGF-β1 dramatically decreased. Our results show that Ramipril reduces fibrosis in the capsule around the implant on histological, immunohistochemical and biochemical analysis. The results of our study may be important for the design of the clinical trials required to investigate the effective and safe doses of Ramipril, which is an inexpensive and easily tolerated drug, on human.Abstract 2049; Table 1The comparison of histological, immunohistochemical and biochemical Results of implant, implant + radiation and ramipril + implant + radiation groupsImplantp value*Implant + RadiationRamipril + Implant + Radiationp value**Capsular thickness (μm)163±35<0.003193±45115±25<0.001Fibrotic area (%)52±9<0.00164±1243±11.5<0.001TGF-β1 (%)28±5<0.00842±823±5<0.001MMP-2 (%)18±5117±4.518±51TIMP-2 (%)22±50.72325±419±5<0.001MMP-2/TIMP-2 ratio (%)0.85±0.30.4730.7±0.21.05±0.5<0.002After the experiment TGF-β1 levels (pg/ml)66±16179.5±2647±70.095Plasma TGF-β1 alteration value (pg/ml)29±15141±246±90.037* p value is statistical difference of between implant and implant + radiation groups ** p value is statistical difference of between implant + radiation and ramipril + implant + radiation groups Open table in a new tab