Simvastatin induces heme oxygenase-1 expression but fails to reduce inflammation in the capsule surrounding a silicone shell implant in rats.
BACKGROUND
Statins are lipid-lowering agents that are widely used in medical practice. Some studies have demonstrated that statins reduce proinflammatory signaling and have antioxidant and anti-inflammatory effects. The inducible heme oxygenase-1 (HO-1) catalyzes the stepwise degradation of heme to produce equimolar quantities of biliverdin, iron, and carbon monoxide; it has also been suggested to promote the important cholesterol-independent cytoprotective action of statins against oxidative insults. However, overexpression of HO-1 may have dual effects under oxidative stress, and the overaccumulation of ferric iron from heme may result in detrimental rather than cytoprotective effects. This study was designed to investigate the effect of a specific statin, simvastatin, and the role of HO-1 on the inflammatory status of the capsule surrounding a silicone shell implant in rats.


METHODS
Sprague-Dawley rats were randomly assigned to different groups according to the indicated implantation time (1 , 2 wk, 1 , 2 , and 3 mo postimplant) and the presence or absence of additional treatment (2 mg/kg oral simvastatin daily and/or 2 mg/kg HO inhibitor zinc protoporphyrin (ZnPP) by intraperitoneal injection daily). The formed de novo capsular tissue around the silicone implant was dissected away at the indicated time of sacrifice for experiments regarding the HO-1 expression and the inflammatory status.


RESULTS
We found a biphasic pattern of inflammation of the capsule with increased production of TNF-α, IL-1β, and COX-2, and activation of NF-κB at 1 wk and again at 1 mo postimplantation. Numerous CD68+monocytes or macrophages were diffusely distributed in the capsule in the early stage but not in the late stage postimplantation. In addition, the implantation procedure induced HO-1 expression, which was significantly up-regulated in the first 2 wk but decreased after 1 mo. Although daily feeding of the rats with simvastatin at 2 mg/kg induced HO-1 expression in the capsule throughout the experimental period, simvastatin treatment failed to reduce the production of TNF-α, IL-1β, and COX-2, or limit NF-κB activation in the early or late stages after implantation. Additionally, simvastatin treatment did not decrease the amount of CD68+cells distributed in the capsule at 1 wk postimplantation. HO-1 up-regulation by simvastatin treatment or down-regulation by additional injection of ZnPP did not demonstrate significant correlation with the inflammatory status of the capsule.


CONCLUSIONS
Simvastatin failed to reduce inflammation of the capsule surrounding a silicone shell implant. Although simvastatin induced HO-1 expression throughout the experimental time, up-regulated HO-1 expression could not be attributed to the inflammatory status of the capsule.
Hsieh
Ching-Hua
CH
Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan.
Sun
Cheuk-Kwan
CK
Lu
Tsu-Hsiang
TH
Chen
Yi-Chun
YC
Lin
Chia-Jung
CJ
Wu
Chia-Jung
CJ
Rau
Cheng-Shyuan
CS
Jeng
Seng-Feng
SF
D000818:Animals; D018427:Breast Implants / Q000009:adverse effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005549:Foreign-Body Reaction / Q000188:drug therapy* / Q000209:etiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000627:therapeutic use*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D019821:Simvastatin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat