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HMG-CoA reductase inhibitors (Statins): A novel approach to preventing hypertrophic scar formation
Jason H. Ko, MD, Yanan Zhao, MD, Seok Jong Hong, PhD, Xian-zhong Ding, MD, PhD, Peter S. Kim, MD, Sonya P. Agnew, MD, Mauricio de la Garza, MD, Thomas A. Mustoe, MD.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Purpose: HMG-CoA reductase inhibitors, also known as “statins,” are the most commonly prescribed cholesterol-lowering medications in the world. There were over 200 million prescriptions, representing $14 billion in sales, for statin treatment in the US in 2009 alone. Simvastatin has been shown to inhibit connective tissue growth factor (CTGF) gene and protein expression, but this has never been proven in an in vivo model. Previous studies in our laboratory have demonstrated that CTGF plays a significant role in wound healing and scarring. Given the potent inhibition of CTGF seen with simvastatin in vitro, we explored whether administration of various statins to healing wounds has any effect on hypertrophic scar formation using an established rabbit ear wounding model.
Methods: Seven-millimeter punch wounds were made on the ears of 31 New Zealand white rabbits, with one ear consisting of 6 treatment wounds and the contralateral ear consisting of 6 control wounds (n=372 total wounds). On post-wounding days 15, 20, and 25, treatment wounds were injected subdermally with either simvastatin, lovastatin, or pravastatin at low (40 µMol), medium (120 µMol), or high doses (400 µMol), whereas control wounds were injected with vehicle (1:1 EtOH/DMSO) at corresponding doses and time points. All wounds were harvested after 35 days, stained with hematoxylin and eosin, and analyzed using the scar elevation index (SEI), a ratio of cross-sectional scar area to the area of tissue excised to make the wound.
Results: Low-dose simvastatin, lovastatin, and pravastatin each demonstrated significant reductions in SEI when compared to control_21.9% (p=0.03), 25.8% (p=0.02), and 22.8% (p=0.01), respectively. There were no significant differences in SEI in the medium- and high-dose statin groups compared to controls. Analysis of mRNA in a subset of rabbits treated with low-dose simvastatin demonstrated a significant reduction in CTGF expression (p=0.009), consistent with the in vitro work of other laboratories while providing a potential mechanism for the reduction in hypertrophic scarring seen with simvastatin.
Conclusions: HMG-CoA reductase inhibitors, or statins, reduce hypertrophic scar formation via CTGF inhibition when administered at low doses, and the novel application of these commonly prescribed medications may lead to innovative and effective anti-scarring therapies.
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