J Korean Med Sci.  2016 Aug;31(8):1273-1278. 10.3346/jkms.2016.31.8.1273.

Simvastatin Reduces Capsular Fibrosis around Silicone Implants

• Chung KJ
• Park KR
• Lee JH
• Kim TG
• Kim YH

• KMID: 2373756
• DOI: http://doi.org/10.3346/jkms.2016.31.8.1273

Abstract

Capsular fibrosis and contracture occurs in most breast reconstruction patients who undergo radiotherapy, and there is no definitive solution for its prevention. Simvastatin was effective at reducing fibrosis in various models. Peri-implant capsular formation is the result of tissue fibrosis development in irradiated breasts. The purpose of this study was to examine the effect of simvastatin on peri-implant fibrosis in rats. Eighteen male Sprague-Dawley rats were allocated to an experimental group (9 rats, 18 implants) or a control group (9 rats, 18 implants). Two hemispherical silicone implants, 10 mm in diameter, were inserted in subpanniculus pockets in each rat. The next day, 10-Gy of radiation from a clinical accelerator was targeted at the implants. Simvastatin (15 mg/kg/day) was administered by oral gavage in the experimental group, while animals in the control group received water. At 12 weeks post-implantation, peri-implant capsules were harvested and examined histologically and by real-time polymerase chain reaction. The average capsular thickness was 371.2 μm in the simvastatin group and 491.2 μm in the control group. The fibrosis ratio was significantly different, with 32.33% in the simvastatin group and 58.44% in the control group (P < 0.001). Connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 gene expression decreased significantly in the simvastatin group compared to the control group (P < 0.001). This study shows that simvastatin reduces radiation-induced capsular fibrosis around silicone implants in rats. This finding offers an alternative therapeutic strategy for reducing capsular fibrosis and contracture after implant-based breast reconstruction.

Keyword

Simvastatin; Fibrosis; Implant Capsular Contracture

MeSH Terms

Administration, Oral
Animals
Breast/*drug effects/metabolism/pathology/radiation effects
*Breast Implants
Connective Tissue Growth Factor/genetics/metabolism
Fibrosis
Gamma Rays
Male
Rats
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Silicone Gels/*chemistry
Simvastatin/*pharmacology
Transforming Growth Factor beta1/metabolism
Connective Tissue Growth Factor
Silicone Gels
Simvastatin
Transforming Growth Factor beta1

Figure

• 

  Fig. 1 Capsules were Masson trichrome stained and imaged at 40 × (A, B) and 100 × (C, D). Representative histologic sections of capsular fibrosis from the control (A, C) and the simvastatin groups (B, D). The collagen fibers of capsule showed a dense parallel pattern in the control group and a loose pattern in the simvastatin group. The bidirectional arrow shows capsule thickness; scale bar, 1,000 μm.

• 

  Fig. 2 The fibrosis ratio was significantly different at 32.33% ± 10.38% in the simvastatin group and 58.44% ± 15.69% in the control group (P < 0.001).

• 

  Fig. 3 Quantitative analysis by real-time PCR showed that CTGF gene expression in the simvastatin group (0.46 ± 0.15) decreased significantly compared to the control group (0.90 ± 0.16) (P < 0.001, A). TGF-β1 gene expression in the simvastatin group (0.50 ± 0.16) decreased significantly compared to the control group (1.00 ± 0.24) (P < 0.001, B).

• 

  Fig. 4 Intracellular mechanism of the inhibition of RhoA signaling by simvastatin. Simvastatin inhibits HMG-CoA reductase, thus, depleting the cellular pool of isoprene precursor molecules, such as FPP and GGPP. Isoprene precursor molecules are required for the prenylation of RhoA GTPase. Subsequent loss of RhoA signaling activity blocks the production of CTGF, which is required for fibrosis. CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; GDP, guanosine 5'-diphosphate; GTP, guanosine 5'-triphosphate.

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