PURPOSE: Breast capsule contracture is the most common complication arising from breast reconstruction with prosthetic materials. The purpose of this study was to examine the role of the Rho inhibition in breast capsule formation. The Rho pathway, which includes small GTPases such as RhoA and protein kinases such as Rho kinase, is important in the wound healing process and regulates two molecular processes that we believe directly underlie capsular contracture: extracellular matrix production and myofibroblast proliferation and contractility. Inhibition of this pathway would therefore be expected to downregulate the markers for fibrosis and contracture in breast capsule formation. METHODS: The degree of capsule formation in animal models receiving Rho inhibition was assessed by histologic examination and measurement of collagen I and smooth muscle actin levels. Silicon implants 2.5 cm in diameter were placed dorsally beneath the panniculus carnosus of 20 Sprague-Dawley rats. Group 1 (n=10) received a local injection of the delivery vehicle (25% Pluronic gel) only at the site of the implant every 2 days for 6 weeks. Group 2 (n=10) received a local injection of 10 uM Rho kinase inhibitor (Y-27632) suspended in 25% Pluronic gel at the site of the implant. At 6 weeks capsules were harvested, grossly examined, stained with hematoxylin-eosin and Masson's trichrome reagent, and subjected to Western blot analysis with anti-collagen I and SMA antibodies. RESULTS: The capsules obtained did not vary considerably in thickness between the 2 groups. This finding was attributed to the limitations of the animal model, which displayed limited scarring and contracture in both groups. However, Trichrome Masson staining revealed that Rho kinase inhibition led to a statistically significant (p< 0.05) decrease in collagen content in the experimental group (Fig 1). Similarly, Western blot analysis showed that the expression of collagen I decreased in conjunction with RhoA expression in response Rho inhibition (Fig 2a,c). The results for smooth muscle actin were equivocal (Fig 2b). CONCLUSIONS: The decrease in collagen staining by Trichrome Masson and the downregulation of RhoA and collagen I expression in the Rho inhibitor treatment group suggest that Rho kinase inhibition mitigates the molecular processes that underlie capsule formation. In light of these findings, the Rho kinase pathway may prove to be a useful target in the prevention of capsular contracture. Further studies with an improved capsule contracture model are being conducted to clarify the relationship between the Rho pathway and smooth muscle actin expression in capsule contracture.

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