Scarring and fibrosis is accompanied by significant morbidity and loss of function. In dermal wounds and fibrotic lesions, a subset of circulating monocytes are recruited to the wound and differentiate into fibroblast-like cells called fibrocytes. A serum protein, serum amyloid P (SAP), can prevent this differentiation in vitro. In vivo, systemic administration of SAP reduced fibrosis in rat and mouse models of bleomycin-induced pulmonary fibrosis and in a murine ischemia-reperfusion model of cardiac fibrosis. We found that systemic administration or local injections of SAP caused delayed wound contraction and healing, and decreased myofibroblast content in murine dermal wounds. Using the female red Duroc pig (FRDP) model of hypertrophic scarring, we have preliminary data indicating that local injection of SAP into deep dermal wounds appears to reduce scarring and the collagen content of these wounds. Based on these observations, we propose to evaluate the role of SAP in wound fibrosis. The key hypothesis of this study is that SAP reduces the fibrotic response in an animal model of hypertrophic scar. To test this hypothesis, we propose the following specific aims: 1: Determine if FRDPs form excessive scars due to either abnormally low serum SAP levels or an abnormal response of fibrocyte precursors to SAP. FRDP serum SAP levels, the sera's ability to inhibit fibrocyte differentiation, and the rate of fibrocyte differentiation by FRDP monocytes will be compared with control Yorkshire pigs. 2. Characterize the effect of SAP on the dermal healing response of FRDP. The effect of intradermal injection of SAP on the healing of deep wounds on FRDP will be assessed by histological, immunohistochemical and molecular analysis of the wounds. 3: Determine the effects of different routes of administration of SAP on the wound healing response. The effect of systemic and local administration of SAP on wound healing will be compared. This highly focused study will evaluate the effect of this serum protein on the complex wound healing process. If our hypothesis proves to be correct, the impact would be substantial and significant, as we might be able to use SAP to prevent excessive scarring not only in hypertrophic scars and keloids but other fibrotic skin conditions and fibrosis in general. PUBLIC HEALTH RELEVANCE: Scar formation in the skin or internal organs can result in loss of function or severe disfigurement with a substantial emotional and financial cost to the individual and society at large. Modalities to treat or prevent scar formation would help reduce the disability resulting from these conditions. This project will evaluate the effect of a naturally occurring protein in the prevention of excessive scarring. Findings of this study would impact our treatment and/or prevention of scarring, be it of the skin, muscle or internal organs.

R21AR055169

2009-04-01

2012-03-31